2-{8 {60 -Alkoxy-arylmethyl{9 -2-imidazolines and -1,4,5,6-tetrahydropyrimidines

ABSTRACT

2-( Alpha -(Lower-alkoxy)- Alpha -R1-Ar-methyl)-2-imidazolines, -1,4,5,6-tetrahydropyrimidines and -4,5,6,7-tetrahydro-1H-1,3diazepines, having pharmacological properties, e.g., hypoglycemic, diuretic, anti-inflammatory, are prepared by heating a 2-(lower-alkoxy)-2-Ar-alkanenitrile with an alkanediamine, wherein 2, 3 or 4 carbon atoms respectively intervene between the two amino groups, in the presence of a catalytic amount of carbon disulfide or hydrogen sulfide, where R1 is hydrogen, lower-alkyl or lower-alkenyl, Ar is phenyl, naphthyl, indanyl, biphenylyl, cyclohexenyl, cyclohexyl and phenyl substituted by from one to three substituents selected from lower-alkyl, lower-alkoxy, halo, trihalomethyl, loweralkylmercapto, lower-alkylsulfonyl, di-(lower-alkyl)amino, amino, hydroxy, nitro, hydroxyamino and benzyloxy. The intermediate 2(lower-alkoxy)-2-Ar-alkanenitriles are prepared preferably by first reacting an aldehyde of the formula Ar-CHO with a tri(lower-alkyl) orthoformate to form the aldehyde di-(lower-alkyl) acetal, reacting the latter with an acyl halide to form the corresponding Alpha -halo-Ar-methyl lower-alkyl ether and reacting said ether with an alkali cyanide to yield said intermediate nitrile.

United States Patent [1 1 Bailey [451 July 29,1975

[ 5 4 2-[a-ALKOXY-ARYLMETHYL] -2- IMIDAZOLINES AND-1,4,5,6-TETRAHYDROPYRIMIDINES Denis M. Bailey, East Greenbush, NY.

Related U.S. Application Data [63] Continuation-impart of Ser. No.26,787, April 8, 1970, abandoned, which is a continuation-in-part ofSer. No. 726,212, May 2, 1968, Pat. NO. 3,657,229.

[75] Inventor:

[30] Foreign Application Priority Data Apr. 24, 1969 United Kingdom20118/69 [52] U.S. Cl....260/251 R; 260/256.4 H; 260/256.5 R;

260/309.6; 424/251; 424/273 [51] Int. Cl. C07D 239/06 [58] Field ofSearch 260/251 R, 256.4 H, 309.6

[56] References Cited UNITED STATES PATENTS 12,919,274 12/1959 Faust eta1. 260/251 Primary Examiner-Donald G. Daus Assistant ExaminerRaymond V.Rush Attorney, Agent, or Firm-Robert K. Bair; B. Woodrow Wyatt [57]ABSTRACT 2-[a-(Lower-alkoxy)-a-R,-Ar-methyll-2-imidazolines,-1,4,5,6-tetrahydropyrimidines and -4,5.6,7- tetrahydro-l H-l,3-diazepines, having pharmacological properties, e.g., hypoglycemic,diuretic, antiinflammatory, are prepared by heating a2-(loweralkoxy)-2-Ar-alkanenitrile with an alkanediamine, wherein 2, 3or 4 carbon atoms respectively intervene between the two amino groups,in the presence of a catalytic amount of carbon disulfide or hydrogensulfide, where R is hydrogen, lower-alkyl or loweralkenyl, Ar is phenyl,naphthyl, indanyl, biphenylyl, cyclohexenyl, cyclohexyl and phenylsubstituted by from one to three substituents selected from loweralkyl,lower-alkoxy, halo, trihalomethyl, loweralkylmercapto,lower-alkylsulfonyl, di-(loweralkyl)amino, amino, hydroxy, nitro,hydroxyamino and benzyloxy. The intermediate 2-(lower-alkoxy)-2-Ar-alkanenitriles are prepared preferably by first reacting analdehyde of the formula Ar-CHO with a tri- (lower-alkyl) orthoformate toform the aldehyde di- (lower-alkyl) acetal, reacting the latter with anacyl halide to form the corresponding a-halo-Ar-methyl lower-alkyl etherand reacting said ether with an alkali cyanide to yield saidintermediate nitrile.

21 Claims, No Drawings 2-(a-ALKOXY-ARYLMETHYL)-2-IMIDAZOLINES AND-1,4,5,GTETRAHYDROPYRIMIDINES This application is a continuation-in-partof my copending application Ser. No. 26,787, filed Apr. 8, 1970 and nowabandoned, which in turn is a continuation-inpart of copendingapplication Ser. No. 726,212, filed May 2, 1968 and now US. Pat. No.3,657,229, issued Apr. I8, 1972.

This invention relates to compositions of matter known in the art ofchemistry as 2-benzyl-l,3-diaza- 2,3-cycloalkenes and analogs thereof,and to their preparation.

The invention in its composition aspect resides in the compounds havingthe formula I where R is alkyl having from two to six carbon atoms, R ishydrogen or lower-alkyl, R is hydrogen or loweralkyl, Y is alkylene of2-8 carbon atoms in which 2 or 3 carbon atoms intervene between thevalence linkages, and Ar is phenyl, naphthyl, indanyl, biphenylyl,cyclohexenyl, cyclohexyl and phenyl substituted by from one to threesubstituents selected from loweralkyl, lower-alkoxy, halo,trihalomethyl, loweralkylmercapto, lower-alkylsulfonyl,di-(loweralkyl)amino, amino, hydroxy, nitro, hydroxyamino and benzyloxy,said compounds being, respectively, 2- imidazolines andl,4,5,6-tetrahydropyrimidines. The compounds of this composition aspectof the invention, when tested according to standard pharmacologicalevaluation procedures in animals, have been found to possess theinherent applied use characteristics of having pharmacologicalproperties, e.g., anti-inflammatory and hypoglycemic activities.Further, said tetrahydropyrimidines of the invention have been found tohave diuretic activity, as determined by standard pharmacologicalprocedures.

Preferred compounds of formula 1 are those where R is ethyl.

The terms lower-alkyl and lower-alkoxy, as used herein, respectively,mean alkyl and alkoxy radicals having from 1 to 6 carbon atoms which canbe arranged as straight or branched chains, among which are, forpurposes of illustration but without limiting the generality of theforegoing, methyl, ethyl, n-propyl, isopropyl, sec-butyl, isobutyl andn-hexyl for lower-alkyl; and, by methoxy, cthoxy, n-propoxy, isopropoxy,isobutoxy, n-amoxy and n-hexoxy for lower-alkoxy.

The compounds of formula I are prepared by the process which comprisesheating a 2-(lower-alkoxy)-2-Aralkanenitrile of formula ll with analkanediamine of the formula Ill in the presence of a catalytic amountof carbon disulfide or hydrogen sulfide, where R, R, R, Y and Ar havethe meanings given hereinabove for formula I.

In the above-described process where Ar is phenyl and the alkanediamineof formula III has 2 or 3 carbon atoms intervening between the valencelinkages of alkylene (Y), i.e., between the two amino nitrogen atoms,the resulting products are, respectively, 2-[01-(lower-alkoxy)benzyl]-2-imidazolines or Z-[a-(loweralkoxy )benzyl]-l,4,5 ,6-tetrahydropyrimidines.

The alkanediamine of formula Ill used in the above condensation can havea hydroxy of lower-alkoxy substituent on a carbon atom not bearing anamino group, and the use of such diamines gives rise, for example, to2-[a-(loweralkoxy)benzyl]-l,4,5,6-tetrahydropyrimidines having hydroxyor lower-alkoxy in the Y portion of formula I where Ar is phenyl.

The final products of formula I are useful in the free base form or inthe form of their acid-addition salts, and both forms are within thepurview of the invention, and are considered to be one and the sameinvention, The acid-addition salts are simply a more convenient form foruse; and, in practice, use of the salt form inherently amounts to use ofthe base form. The acids which can be used to prepare the acid-additionsalts are preferably those which produce, when combined with the freebase, pharmaceutically acceptable salts, that is, salts whose anions arerelatively innocous to the animal organism in pharmaceutical doses ofthe salts, so that the beneficial properties inherent in the free baseare not vitiated by side effects ascribable to the anions; in otherwords, the latter do not substantially affect the pharmaceuticalproperties inherent in the cations. Appropriate pharmaceuticallyacceptable salts within the scope of the invention are preferably thosederived from mineral acids such as hydrochloric acid, hydrobromic acid,hydriodic acid, nitric acid, phosphoric acid, sulfamic acid, andsulfuric acid; and organic sulfonic acids such as methanesulfonic acid,ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,naponic acid (l,4-naphthalenedisulfonic acid), and the like, giving thehydrochloride, hydrobrmide, hydriodide, nitrate, phosphate, sulfamate,sulfate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate and naponate, respectively.

The acid-addition salts are prepared preferably by reacting the freebase and acid in an organic solvent, e.g., ethanol, 2-propanol, acetone,etc., in which case the salt separates directly or can be obtained byconcentration of the solution.

Examination of the final products of formula 1, upon infrared andnuclear magnetic resonance spectographic analyses, reveals dataconfirming the molecular structures assigned to these compounds. Thesedata, taken together with the nature of the starting material, mode ofsynthesis and results of elementary analyses, positively confirm thestructures of the final products.

The manner and process of making and using the invention will now begenerally described so as to enable a person skilled in the art of amedicinal chemistry to make and use the same, as follows:

PREPARATION OF INTERMEDIATES The intermediate2-(lower-alkoxy)-2-Aralkanenitriles (formula 11), examples of which areknown, e.g., 2-ethoxy-2-phenylethanenitrile (ora-ethoxyphenylacetonitrile), 2-methoxy-2- phenylethanenitrile and2-ethoxy-2-(4-methoxyphenyl- )ethanenitrile, are prepared by generallyknown methods. For example, one method found convenient utilized threesteps by first reacting the corresponding generally known aldehydes ofthe formula Ar-C'HO with a tri-(lower-alkyl) orthoformate of the formulaI-IC(OR) to form the corresponding aldehyde di- (lower-alkyl) acetal ofthe formula ArCH(OR)- which is then reacted with a lower-alkanoylhalide, e.g., acetyl chloride, to form the corresponding a-halo-Armethyllower-alkyl ether of the formula Ar-CHC- 1(OR) which in turn is reactedwith a alkali cyanide, e.g., sodium cyanide, to yield thea-(lower-alkoxy)-Aracetonitrile of the formula Ar-CI-I(OR)CN, that is,the compound of formula 11 where R is hydrogen. Reaction of thiscompound with a lower-alkylating agent, e.g., a lower-alkyl halide, inthe presence of a strong base, e.g., potassium tertiary-butoxide,sodamide, etc., yields the compounds of formula 11 where R isloweralkyl.

The compounds of formula II where R is hydrogen also can be prepared bythe generally known method of heating the correspondinga-(lower-alkoxy)-Aracetamide of the formula Ar--CH(OR)CONH with adehydrating agent effective to convert carboxamides to nitriles, e.g.,thionyl chloride. Said oz-(lower-alkoxy)- Ar-acetamides are preparedfrom the corresponding generally known a-(lower-alkoxy)-Ar-acetic acidsby the generally procedures of converting said acids to their acidchloride by reaction with thionyl chloride and reacting said acidchlorides with ammonia to form said carboxamides.

PREPARATION OF FINAL PRODUCTS The final products, as illustrated byformula I, are prepared by heating a 2-(lower-alkoxy)-2-Aralkanenitrileof formula II with an alkanediamine of formula III in the presence ofacatalytic amount of carbon disulfide or hydrogen sulfide. This reactionis carried out by heating the reactants in the presence of the sulfidecatalyst, preferably with stirring under an inert atmosphere, e.g.,nitrogen, at about 70 to 200C., preferably between about 90 and 150C.

Alternatively, and less preferably, the final products can be preparedby heating the corresponding 2-(lower-alkoxy-Z-Ar-alkanoic acid orlower-alkyl ester thereof, preferably methyl or ethyl ester, with saidalkanediamine, e.g., 1,2-ethanediamine or 1,3- propanediamine, generallyat higher temperatures than used with the nitriles, i.e., aboutl40200C., preferably about l40-160C.

The best mode contemplated for carrying out the invention will now beset forth as follows:

A. ALDEHYDE Dl-(LOWER-ALKYL) ACETALS l. Benzaldehyde diethyl acetal Amixture containing 106 g. of benzaldehyde, 161 g. of triethylorthoformate, 138 g. of ethanol and 2 g. of finely powdered ammoniumchloride was refluxed on a steam bath for fifteen minutes; the excessreactants were then distilled off at about 85C.; and the remainingma'teriahwas distilled in vacuo. After a fore-run of ethylorthoformate-(b.p., 40-60C. at 10 mm.), 160 g. of benzaldehyde diethylacetal was collected at 9799C./l0 mm.

2. l-Naphthaldehyde dimethyl acetal T0134 g. of l-naphthaldehyde in aone liter round bottom flask was added successively 120 g. of trimethylorthoformate, 120 ml. of methanol and two drops of concentratedhydrochloric acid. After the initial vigorous reaction had subsided, thesolution was refluxed for 30 minutes and then the excess reagents wereremoved by distilling under reduced pressure. The residue was distilledin vacuo to yield 160 g. of l-naphthaldehyde dimethyl acetal, b.p. 94C.at .12 mm.

3. 2,6-Dichlorobenzaldehydediethyl acetal. 143 g., was prepared bystirring a mixture containing 100 g. of 2,o-dichlorobenzaldehyde, 90 g.of triethyl orthoformate, 90 ml. of ethanol and 0.5 ml. of concentratedhydrochloric acid for 45 minutes at room temperature (2530C.), forforty-five minutes on a steam bath and then 1 hour at room temperature,followed by removal of the excess reactants by distilling in vacuo at C.using a water pump. The product was used in the next step without anyfurther purification.

4. 2-Chlorobenzaldehyde diethyl acetal, 835 g., as a clear pale yellowoil, was prepared as in Example A-3 using 500 g. of2-chlorobenzaldehyde, 634 g. of triethyl orthoformate, 625 ml. ofethanol and 1 ml. of concentrated hydrochloric acid.

5. 4-Chlorobenzaldehyde diethyl acetal, 168.5 g., b.p. l26-129C. at 15mm., was prepared by refluxing for 30 minutes a mixture containing 140.6g. of 4- chlorobenzaldehyde, 178 g. of triethyl orthoformate, 175 ml. ofethanol and 1 ml. of concentrated hydrochloric acid; distilling off invacuo (at C. using a water pump) the solvent and excess reactants; and,distilling the residue under high vacuum.

6. Indane-S-carboxaldehyde diethyl acetal, 281 g., b.p. l39-l40C. at 9mm., was prepared as in Example A-5 using 200 g. ofindane-S-carboxaldehyde, 244 g. of triethyl orthoformate, 200 ml. ofabsolute ethanol, 1 ml. of concentrated hydrochloric acid and a refluxperiod of 1 hour.

7. l-Naphthaldehyde diethyl acetal, 197 g., b.p. l00l0l at 0.16-0.17mm., was prepared as in Example A-2 using 156.2 g. of l-naphthaldehyde,196 g. of triethyl orthorformate, ml. of ethanol and two drops ofconcentrated hydrochloric acid.

8. 3-Fluorobenzaldehyde diethyl acetal, 140.8 g. b.p. 9l-95C. at 10 mm.,was prepared as in Example A-5 using 124. g. of 3-fluorobenzaldehyde,163 g. of ethyl orthoformate, m1. of absolute ethanol, three drops ofconcentrated hydrochloric acid and a reflux period of 30 minutes afterthe 3f1uorobenzaldehyde had been added in'three equal portions withstirring to the other reactants.

9. 4-Isopropylbenzaldehyde diethyl acetal, 198.1 g., was prepared as inExample A-3 using 148 g. of 4-isopropylbenzaldehyde, g. of triethylorthoformate, 150 ml. of absolute ethanol, 2 ml. of concentratedhydrochloric acid and a reflux period of 1 hour after mixing thereactants.

l0. 4-Methoxybenzaldehyde diethyl acetal, 422 g., was prepared as inExample A-9 using 242 ml. of 4- methoxybenzaldehyde (anisic aldehyde),326 g. of triethyl orthoformate, 250 ml. of absolute ethanol and sixdrops of concentrated hydrochloric acid.

l 1. Benzaldehyde dimethyl acetal, 146.2 g., b.p. 98-103C. at 31-37 mm.,was prepared as in Example A-5 using 106.1 g. of benzaldehyde, 127.5 g.of triethyl orthoformate, 96.1 g. of anhydrous methanol and one drop ofconcentrated hydrochloric acid.

12. 4-Methylbenzaldehyde diethyl acetal, 387 g., was prepared as inExample A-3 using 240 g. of 4- methylbenzaldehyde. 296 g. of triethylorthoformate. 350 ml. of absolute ethanol and six drops of concentratedhydrochloric acid. allowing the reactants to stand for minutes aftermixing before heating on a steam bath for about thirty minutes.

13. 2-Naphthaldehyde diethyl acetal, 102.4 g., b.p. l05-l08C. at 0.02mm., was prepared as in Example A-5 using 90 g. of 2-naphthaldehyde,121.5 g. of triethyl orthoformate, 90 ml. of absolute ethanol and twodrops of concentrated hydrochloric acid, stirring the reactants forabout 30 minutes and then refluxing for 45 minutes.

14. 3,4-Dichlorobenzaldehyde diethyl acetal A mixture containing 175 g.of 3,4- dichlorobenzaldehyde, 178 g. of triethyl orthoformate, 100 ml.of absolute ethanol and 100 ml. of 5% ethanolic hydrogen chloridesolution was stirred under reflux for 30 minutes. The reaction mixturewas then cooled and neutralized with sodium ethoxide solution preparedfrom 2.3 g. of sodium and 100 ml. of absolute ethanol. The solvent wasdistilled off in vacuo; the residue was cooled in an ice bath anddiluted with 300 ml. of benzene; and, the resulting mixture was pouredinto 200 ml. of cooled 10% aqueous sodium hydroxide solution. Thebenzene layer was separated, washed with 200 ml. of water, dried overanhydrous sodium sulfate, filtered through anhydrous sodium sulfate andheated on a steam bath in vacuo to remove any solvent. The residue wasthen distilled in vacuo to yield a 201.7 g. fraction of3,4-dichlorobenzaldehyde diethyl acetal, b.p. 7388C. at 0185-0310 mm.

15. Benzaldehyde di-n-propyl acetal A mixture containing 210 g. ofbenzaldehyde dimethyl acetal, 1 liter of n-propanol and 1 drop ofconcentrated hydrochloric acid was fractionally distilled through a 9inch column packed with glass helices. After removing the methanol atatmospheric pressure, then removing the excess n-propanol using a rotaryevaporator, the product, benzaldehyde di-n-propyl acetal b.p. 242245C.,was distilled at atmospheric pressure.

16. Benzaldehyde di-n-butyl acetal, 247.3 g., b.p. ll2-l C. at 1.7 mm.,was prepared using the procedure of Stewart et a1. [JACS 77, 1098(1955)]using 202 ml. of benzaldehyde, 600 ml. of n-butanol and two drops ofconcentrated hydrochloric acid.

17. 2-Methoxybenzaldehyde diethyl acetal 105 g., was prepared as inExample A-3 using 65 g. of 2- methoxybenzaldehyde, 90 g. of triethylorthoformate, 200 ml. of absolute ethanol and 1 ml. of concentratedhydrochloric acid.

18. 4-Benzyloxybenzaldehyde diethyl acetal To a suspension containing100 g. of 4-benzyloxybenzaldehyde, 90 g. of triethyl orthoformate and250 ml. of absolute ethanol was added 1 ml. of concentrated hydrochloricacid. After allowing the reaction mixture to stand for one hour at about2530C., 30 g. of solid potassium carbonate was added and the resultingmixture was stirred for 5 minutes and filtered.

The filtrate was evaporated in vacuo to yield g. of4-benzyloxybenzaldehyde diethyl acetal.

l9. 3-Cyclohexenealdehyde diethyl acetal To a stirred solutioncontaining 128.5 g. of 3- cyclohexenealdehyde l,2,3,6-tetrahydrobenzaldehyde) and 250 ml. of absolute ethanol was addedsuccessively in few mg. of p-toluenesulfonic acid and 220 ml. oftriethyl orthoformate, the latter at such a rate to maintain thereaction temperature at about 38C. (aided by cooling in an ice bath).The reaction mixture was stirred at room temperature for 17 hours.warmed on a steam bath to reflux (reaction temperature 78C.) for 2hours, cooled and distilled in vacuo to remove the ethanol and excesstriethyl orthoformate. The remaining viscous yellow oily residue wasdissolved in 500 ml. of ether and the solution extracted successivelywith 10% aqueous sodium hydroxide solution 3 times and then with water.The ether solution was then dried over anhydrous magnesium sulfate andthe ether removed by distilled in vacuo, thereby yielding 208 g. of 3-cyclohexenealdehyde diethyl acetal.

20. 3-Fluoro-4-methoxybenzaldehyde diethyl acetal, 192 g., was preparedas in Example A-3 using 122 g. of 3-fluoro-4-methoxybenzaldehyde, g. oftriethyl orthoformate, 200 ml. of absolute ethanol and three drops ofconcentrated hydrochloric acid.

B. ALPHA-HALO-Ar-METHYL LOWER-ALKYL ETHERS 1. a-Chlorobenzyl ethyl etherA mixture containing 157 g. of benzaldehyde diethyl acetal, g. of acetylchloride and 1.5 ml. of thionyl chloride was stirred at room temperature(25-30C.) overnight (about 15 hours). The volatile liquids (excessacetyl chloride and ethyl acetate) were removed under reduced pressureand the residue was fractionated in vacuo to yield 139.5 g. ofa-chlorobenzyl ethyl ether, b.p. 5860C. at 0.2 mm.

2. a,3,4-Trichlorobenzyl ethyl ether, 218.2 g., was prepared as inExample B-l using 229.5 g. of 3,4- dichlorobenzaldehyde diethyl acetal,393 ml. of acetyl chloride and 3.5 ml. of thionyl chloride. The ether,not distilled, was obtained after removal of volatile liquids from thereaction mixture and heating the residue at 100C. and 0.07 mm.

3. l-Naphthylchloromethyl methyl ether A mixture containing 160 g. ofl-naphthaldehyde dimethyl acetal and 280 m1. of acetyl chloride in aflask equipped with a reflux condenser and a calcium chloride tube wasallowed to stand at room temperature overnight. The excess acetylchloride and the methyl acetate formed during the reaction were removedin vacuo at 30C. to yield 160 g. of lnaphthylchloromethyl methyl ether.

4. a-Chlorobenzyl methyl ether, 131.7 g., was prepared as in Example B-3using 146.2 g. of benzaldehyde dimethyl acetal and 408 ml. of acetylchloride.

5. 0:,4-Dichlorobenzyl ethyl ether To a stirred mixture containing 280ml. of acetyl chloride and 2 ml of thionyl chloride was added dropwiseat about 30C. 168.5 g. of 4-chlorobenzaldehyde diethyl acetal over aperiod of about 40 minutes. The reaction mixture was then allowed tostand overnight at room temperature. The solvent was removed in vacuo ata temperature below 40C. and then the residue was heated invacuo at 50C.for about 30 minutes to yield 152 g. of a,4-dichlorobenzyl ethyl ether.

6. a,2,6-Trichlorobenzyl ethyl ether. 139 g was prepared as in ExampleB- using 143 g. of 2,6- dichlorobenzaldehyde diethyl acetal, 200 ml. ofacetyl chloride and 100 ml. of thionyl chloride. A g. sample distilledat 8283C. at 0.06 mm.

7. a,2-Dichlorobenzyl ethyl ether, 826 g., was prepared as in ExampleB-5 using 835 g. of 2- chlorobenzaldehyde diethyl acetal, 1260 ml. ofacetyl chloride and 2 ml. of thionyl chloride.

8. a-Chloro-3-fluorobenzyl ethyl ether To 330 ml. of acetyl chloridecontaining 1 ml. of ethanol was added dropwise with stirring over aperiod of about 1 hour 184 g. of 3-fluorobenzaldehyde diethyl acetal,keeping the temperature between about 30C. by intermittent cooling withand ice bath. The solution was allowed to stand overnight at roomtemperature and then heated in vacuo below 40C. to remove the excessacetyl chloride and ethyl acetate. The residue was then heated in vacuoat 50C. for an hour to yield 175 g. of a-chloro-3-fluorobenzy1 ethylether.

9. a-Chloro-4-methoxybenzyl ethyl ether, 401 g., was prepared as inExample B-8 using 422 g. of 4- methoxybenzaldehyde diethyl acetal, 357ml. of acetyl chloride and l ml. of ethanol.

10. aCh1oro-2-naphthy1methyl ethyl ether, 101 g., was prepared as inExample B-8 using 106 g. of 2- naphthaldehyde diethyl acetal and 82 ml.of acetyl chloride.

11. a-Chloro-l-naphthylmethyl ethyl ether, 187 g., was prepared as inExample 13-8 but using 2 ml. of thionyl chloride together with 350 ml.of acetyl chloride and 196.5 g. of l-naphthaldehyde diethyl acetal.

12. a-Chloro-4-isopropylbenzyl ethyl ether, 189 g., was prepared as inExample B-8 using 198 g. of 4-isopropylbenzaldehyde diethyl acetal, 160ml. of acetyl chloride and 1 ml. of ethanol.

13. oz-Chlorobenzyl-n-propyl ether, 92.4 g., was prepared as in ExampleB-8 using 104 g. of benzaldehyde I di-n-propyl acetal and 178 m1. ofacetyl chloride.

14. a-Chlorobenzyl n-butyl ether, 198 g.. was prepared as in Example B-8using 236 g. of benzaldehyde di-n-butyl acetal, 178 m1. of acetylchloride and a few drops of ethanol.

15. a-Ch1oro-4-methylbenzyl ethyl ether, 185 g., was prepared as inExample B-8 using 194 g. of 4- methylbenzaldehyde diethyl acetal, 284ml. of acetyl chloride and 3 ml. of thionyl chloride.

16. a-Chloro-S-indanylmethyl ethyl ether, 104 g., was prepared as inExample B-8 using 281 g. of indane-S-carboxaldehyde diethyl acetal and400 m1- of acetyl chloride. 7

17. a-Chloro-Z-methoxybenzyl ethyl ether, 96 g., was prepared as inExample B-5 using 105 g. of 2- methoxybenzaldehyde diethyl acetal, 160ml. of acetyl chloride and 1 ml. of thionyl chloride.

18. 4-Benzyloxy-a-chlorobenzyl ethyl ether was prepared as in ExampleB-8 using 135 g. of 4-benzyloxybenzaldehyde diethyl acetal. 106 ml. ofacetyl chloride and 1 ml. of thionyl chloride.

19. oz-Chloro-l,2,3,6-tetrahydrobenzyl ethyl ether, 156 g., was preparedas in Example B-8 using 198 g. of l,2.3,6-tetrahydrobenzaldehyde diethylacetal, 700 ml. of acetyl chloride and 1 ml. of thionyl chloride.

20. a-Chloro-3-fluoro-4-methoxybenzyl ethyl ether, 176 g.. was preparedas in Example B-8 using 192 g. of

3-fluoro-4-methoxybenzyaldehyde diethyl acetal. 500 g.'of acetylchloride and 1 ml. of thionyl chloride.

C. ALPHA-(LOWER-ALKOXY)-Ar-ACETON1TR1LES FROM ALPHAHALO-Ar-METHYLLOWER-ALKYL ETHERS 1. a-Ethoxyphenylacetonitrile To a suspensioncontaining 37.8 g. of sodium cyanide in 400 ml. of dimethylformamide wasadded dropwise with stirring over a period of about 45 minutes, keepingthe mixture below C., a solution containing 105 g.

of a-chlorobenzyl ethyl ether in 100 ml. of dimethylformamide. Themixture was stirred for an additional 15 thirty minutes; the solids werefiltered off; the solvent was distilled off under reduced pressure; and,the residue was fractionally distilled to yield 66 g. ofa-ethoxyphenylacetonitrile, b.p. 1 14-"1 16C. at 10 mm.

2. a-Ethoxy-2,6-dichlorophenylacetonitrile, 63 g., b.p. 97C. at 0.05mm., was prepared as in Example C-l using 36 g. of sodium cyanidesuspended in 250 ml. of dimethylformamide and 124 g. of 01.2.6-dichlorobenzyl ethyl ether and 40 m1. of dimethylformamide. Beforedistillation, infusorial earth was added to the reaction mixture; themixture was filtered; and the filter cake was washed with benzene; and,the filtrate was evaporated on a rotary evaporator. removing the last ofthe dimethylformamide through a fractionating 30 column using a waterpump.

3. a-Ethoxy-Z-chlorophenylacetonitrile To a stirred suspensioncontaining 204 g. of sodium cyanide in 1500 ml. of dimethylformamide wasadded over a period of about two hours, keeping the reaction mixture atabout 2025C.. 676 g. of 01,2-

dichloroben'zyl ethyl ether and the resulting mixture was stirred for anadditional hour. To the reaction mixture was added 800 m1. (dry volume)ofinfusorial earth and the mixture was filtered through infusorialearth. 40 The filter pad was washed with benzene. The combined filtrateand washings were evaporated in vacuo at about 20-40 mm. and 70C. Theresidue was taken up with 1500 ml. of 1:1 benzene-ether and theresulting solution treated with 2 liters of ice water containing 200 m1.5 of 10% aqueous sodium hydroxide solution. The aqueous layer wasdrained off and discarded. The organic layer was washed with two 500 ml.portions of water and with 250 ml. portions of brine, and then driedovernight over anhydrous sodium sulfate. The solvent was distilled offin vacuo and the residue fractionally distilled to yield 379 .2 g. ofa-ethoxy-Z- chlorophenylacetonitrile, b.p. 9397C. at 1.4 mm.

4. a-Ethoxy-4-chlorophenylacetonitrile, 88.5 g., b.p.

103105C. at 1.3 mm., was prepared as in Example C-2 using 49 g. ofsodium cyanide in dimethylformamide and 152 g'. of a,4-dichlorobenzy1ethyl ether.

5. a-Methoxy-l-naphthylacetonitrile, 68 g.. b.p. 124-126C. at 0.27-0.28mm., was prepared as in Example C-3 using 49 g. of sodium cyanide in 500ml. of dimethylformamide and 160 g. of a-chloro-lnaphthylmethyl methylether in 250 ml. of dimethylformamide.

6. a-Ethoxy-3,4-dichlorophenylacetonitrile, 24.5 g. at 7890C. and0015-0025 mm. and 14.9 g. at 100-108C. and 0.05 mm., was prepared as inExample C-l using 50.5 g. of sodium cyanide suspended in 545 ml. ofdimethylformamide and 198.2 g. of (1,3,4-

trichlorobenzyl ethyl ether in 140 ml. of dimethylformamide.

7. a'Methoxyphenylacetonitrile, 55.5 g., b.p. 5968.5"C. at 0.03-0.14mm., was preparedd as in Ex ample C-1 using 51.5 g. of sodium cyanide in553 ml. of dimethylformamide and 131.7 g. of a chlorobenzyl methyl etherin 141 ml. of dimethylformamide.

8. a-n-Propoxyphenylacetonitrile, 57.3 g., b.p. 100 1 03C. at 2 mm., wasprepared as in Example C-3 but using only ether (no benzene) to extractthe product and using 30.6 g. of sodium cyanide in 200 ml. ofdimethylformamide and 92.4 g. of a-chlorobenzyl npropyl ether.

9. a-n-Butoxyphenylacetonitrile, 122.9 g., b.p. l05.5107.5C. at 1.5 mm.,was prepared as in Example C-8 using 61.2 g. of sodium cyanide in 500ml. of dimethylformamide and 198 g. of n-butyl a-chlorobenzyl ether.

10. a-Ethoxy-3-fluorophenylacetonitrile, 54.6 g., b.p. 7S-78C. at 0.17mm., was prepared as in Example C-8 using 57 g. ofsodium cyanide in 600m1. of dimethylformamide and 175 g. of oz-chloro-3fluorobenzyl ethylether.

1 1. a-Ethoxy-4-Methoxyphenylacetonitrile, 299.5 g., b.p. l18-125C. at1.5 mm., was prepared as in Example C-8 using 122.5 g; of sodium cyanidein 900 ml. of dimethylformamide and 401 g. of a-chloro-4- Methoxybenzylethyl ether.

12. a-Ethoxy-2-naphthylacetonitrile, 40.44 g., b.p. 119l21C. at 0.09mm., was prepared as in Example C-8 using 28.2 g. of sodium cyanide in350 ml. of dimethylformamide and 101 g. of a-Chloro-Z- naphthylmethylethyl ether. The product solidified on standing and was found to melt at5254C.

l3. a-Ethoxy-4-isopropylphenylacetonitrile, 109.6 g., b.p. 8692C. at0.10 mm., was prepared as in Example C-8 using 55 g. of sodium cyanidein 400 ml. of dimethylformamide and 189 g. of a-chloro-4-isopropylbenzylethyl ether.

14. a-Ethoxy-l-naphthylacetonitrile, 97.3 g., b.p. l35-139C. at 0.09-0.12 mm., was prepared as in Example C-8 using 50 g. of sodium cyanide in850 ml. of dimethylformamide and 182 g. of a-chloro-lnaphthylmethylethyl ether,

15. a-Ethoxy-4-methylphenylacetonitrile, 89 g., l33l35C. at 9 mm., wasprepared as in Example C-8 using 61 g. of sodium cyanide in 300 m1. ofdimethylformamide and 172 g. of a-chloro-4-methylbenzyl ethyl ether.

16. a-Ethoxy-S-indanylacetonitrile, 104 g., b.p. l22-l26C. at 1.4 m.,was prepared as in Example C-8 using 78.5 g. of sodium cyanide in 650ml. of dimethylformamide and 269.8 g. of a-Chloro-S-indanylmethyl ethylether. Before fractionating, the reaction mixture was diluted with 1300ml. of water, the mixture extracted three times with benzene, theextract washed with water, dried over anhydrous potassium carbonate andevaporated in vacuo to remove the benzene.

l7. a-Ethoxy-2-methoxyphenylacetonitrile, b.p. llll13C. at 1.3 mm., wasprepared as in Example C-8 using 30 g. ofsodium cyanide in 250 ml. ofdimethylformamide and 96 g. of a-chloro-2-methoxybenzyl ethyl ether.

18. 4-Benzyloxy-a-ethoxyphenylacetonitrile To a stirred mixturecontaining 30 g. of sodium cyanide in 250 ml. of dimethylformamide wasadded dropwise over a period of 45 minutes4-benzyloxy-achlorobenzylethyl ether prepared from g. of4-benzyloxybenzaldehyde diethyl acetal (Example B-18), maintaining thereaction temperature at about 20-25C. by slight external cooling. Thereaction mixture was stirred for an additional three hours, infusorialearth was added and the mixture was filtered through infusorial earth.The filter cake was washed successively with dimethylformamide andbenzene. The combined filtrate and washings were evaporated to a lowvolume and was taken up in a mixture of benzene, ether and water. Thelayers were separated and the organic layer was washed three times withwater and then stirred vigorously for one hour with 100 ml. of 1Nhydrochloric acid. The layers were separated and the organic layer waswashed with aqueous sodium biacrbonate solution, dried over anhydrouspotassium carbonate while treating with decolorizing charcoal. themixture filtered and the filtrate evaporated in vacuo to remove theether and benzene. The residue was distilled under reduced pressure toyield 53.7 g. of 4-benzyloxy-aethoxyphenylacetonitrile, b.p. -l58C. at0.03-0.04 mm.

19. a-Ethoxy-3-cyclohexenylacetonitrile, 13.6 g.,

b.p. 9799C., at 8 mm., was prepared as in Example C-3 using 23 g. ofsodium cyanide, 400 ml. of dimethylformamide, 80 g. of a-chloro-l,2,3,6tetrahydrobenzaldehyde ethyl ether and ether instead ofbenzeneether in the work-up.

20. 3-Chloro-a-ethoxyphenylacetonitrile, b.p. 899lC. at 0.14 mm.,67.1lg., was prepared as in Example C-8 using 53.9 g. of sodium cyanide, 300ml. of dimethylformamide and 146 g. of a,3-dichlorobenzyl ethyl ether.

21. a-Ethoxy-3-fluoro-4-methoxyphenylacetonitrile, b.p. l251259C. at 1.4mm., 81.3 g., was prepared as in Example C-8 using 49 g. of sodiumcyanide, 500 ml. of dimethylformamide and 176 g. of a-chloro-3-fluoro-4-methoxybenzyl ethyl ether.

Following the procedure described in Example C. e.g., C-1,C-3 or C-8,using corresponding molar equivalents of the appropriate a-haloAr-methyllower-alkyl ether, the following a-(lower-alkoxy)-Ar-Acetonitriles areprepared: 3-fluoro-a-n-propoxypheny1acet0nitrile usinga-chloro-3-fluorobenzyl n-propyl ether; 2,4-dibromo-a-ethoxyphenylacetonitrile using 2,4-dibromo-ot-chloro'benzylethyl ether; a,3,4-triethoxyphenylacetonitrile using a chloro-3,4-diethoxybenzyl ethyl ether; a-ethoxy-3- diethylaminophenylacetonitrileusing a-chloro-3- diethylaminobenzyl ethyl ether; a-n-butoxy-4-methylmercaptophenylacetonitrile using acetals and then thecorresponding a-halo-Ar-methyl lower-alkyl ether.

D. ALPHA-(LOWER-ALKOXY)-Ar ACETlC AClDS, ESTERS AND AMlDES l.a-Methoxyphenylacetamide A solution of 30 g. of ethyloz-chlorophenylacetate in 100 ml. of 1.6M methanolic sodium methylatewas refluxed for three hours, the solvent stripped off and the residuepartitioned between ether and cold dilute hydrochloric acid.Distillation of dried ether solution yielded 16 g. of ethyla-methoxyphenylacetate, b.p. 130l32C. at 19 mm. This ester was dissolvedin 300 ml. of methanol which previously had been saturated with ammoniaand the solution was allowed to remain at room temperature for 3 days.The solvent was removed and the residue recrystallized from benzene toyield 7.5 g. of a-methoxyphenylacetamide, m.p. l l l-l 12C.

2. ot-Methoxyphenylacetamide To a stirred solution containing 53.5 g. ofbenzaldehyde, 89.5 g. of chloroform and 100 ml. of methanol, maintainedat 4045C., there was added dropwise a solution of 165 g. of potassiumhydroxide in 400 ml. of methanol. After standing at room temperature for14 hours, the reaction mixture was stripped of solvent and the residualmaterial was dissolved in water. The aqueous solution was filteredthrough decolorizing charcoal, and the filtrate was acidified andextracted with ether. Distillation of dried ether solution yielded 44 g.of a-methoxyphenylacetic acid, b.p. 130l34C. at 0.7 mm. and m.p. 6870C.after recrystallizing from benzenepetroleum ether. Thirty grams ofamethoxy phenylacetic acid was added to a mixture of 30 ml. of thionylchloride and 100 ml. of chloroform, and the mixture was refluxed foreight hours. The volatile liquids were removed by distilling in vacuoand the residue was dissolved in a small amount of acetone. The acetonesolution was added slowly to ammonium hydroxide containing ice. Thereaction mixture was distilled in vacuo and the remaining dry residuewas recrystallized from aqueous isopropyl alcohol using decolorizingcharcoal to yield 15.8 g. of a-methoxyphenylacetamide, m.p. l09-l 11C.

3. a-Methoxya-3-trifluoromethylphenylacetamide A solution of 10.4 g. of3-trifluoromethylbenzaldehyde and 17.2 g. of bromoform in 50 ml. ofmethanol was stirred at -5C. while a solution of 18 g. of potassiumhydroxide in 100 ml. of methanol was added over a period of 90 minutes.The mixture was allowed to remain overnight in a melting ice bath andthen most of the alcohol was removed by ether extraction and thesolution acidified. The precipitated oily material was extracted anddistilled to yield 8 g. of a-methoxy-3- trifluoromethylphenylaceticacid, b.p. l20-l22C. at 0.4 mm. This acid was converted into its acidchloride by refluxing a solution of 12 g. of the acid in 25 ml. ofthionyl chloride for 2 hours and removing the excess thionyl chloride byvacuum-distillation. The acid chloride was added slowly to ammoniumhydroxide containing ice and the semi-solid amide was collected andrecrystallized twice from benzenepetroleum ether to yield 4.5 g. ofa-methoxy-3 -trifluoromethylphenylacetamide, m.p. 9697C.

4. a-n-Butoxyphenylacetamide To a stirred solution of 32.4 g. ofbenzaldehyde, 81 g. of bromoform and 100 ml. of n-butanol kept at about-10C. was added dropwise a solution prepared by reacting 34.5 g. ofsodium with 700 ml. of n-butanol. After remaining overnight, the mixturewas distilled to drynessandthe residue taken up in water. The aqueoussolution was clarified by ether extract, acidified and the precipitatedoily acid was extracted with ether and fractionated to yield 14.1 g. ofa-n-butoxyphenylacetic acid. b.p. 130-l 32C. at 0.4 mm. This acid 14 g.)was i combined with 25 ml. thionyl chloride with 50 ml. of

benzene and refluxed for 2 hours. The solvent was removed and theresidue was added to iced ammonium hydroxide to yield 7 g. ofa-n-butoxyphenylacetamide, m.p. 8485C., after recrystallization aftern-heptane.

5. 4-Ch1oro-a-methoxyphenylacetamide, m.p. 133-l 34C., was prepared in37% yield as in Example D-3 using corresponding molar equivalentquantities of 4-chlorobenzaldehyde, bromoform and methanol to form4-chloro-a-methoxyphenylacetic acid, b.p. l48l49C. at 0.5 mm. and m.p.8284C. and converting the acid to its acid chloride using thionylchloride and reacting the acid with ammonia to yield the amide.

6. a-Ethoxyphenylacetamide, b.p. -144C. at 0.4 mm. and m.p. 72-74C.after recrystallization from nheptane, was obtained as in Example D-2first using corresponding molar equivalent quantities of benzaldehyde,chloroform and ethanol in the presence of potassium hydroxide to give a37% yield of a-ethoxyphenylacetic acid, b.p. 137179C. at 0.7 mm; andthen successively converting the acid to its acid chloride with thionylchloride and then to its amide with ammonia.

7. a-Methoxy-4'biphenylylacetic acid To a stirred suspension of 25 g. of4-biphenylcarboxaldehyde, 37.8 g. of bromoform and ml. of methanolstirred at O5C. was added dropwise a solution of 48 g. of 85% potassiumhydroxide in 230 ml. of methanol. About one-half of the potassiumhydroxidemethanol solution was added over a 30 minute period and theremainder was added more rapidly over a 15 minute period. The reactionmixture was stirred in a melting ice bath for about 20 hours andevaporated in vacuo to remove the methanol and water. The residue wastaken up with a mixture of ethyl acetate and water. The aqueous layerwas separated and acidified. The acidic solution was extracted withchloroform and the remaining acidic solution evaporated in vacuo. Theremaining solid residue was crystallized first from ben zene and thenfrom isopropyl alcohol to yield 13.6. g.

of a-methoxy-4-biphenylylacetic acid, m.p. l30.5-133C.

E. ALPHA-( LOWER-ALKOXY )-Ar-ACETONITRILES FROM ALPHA-( LOWER-ALKOXY)-Ar-ACETAMlDES l. a-Methoxyphenylacetonitrile A solution of 7.5 g. ofa-methoxyphenylacetamide in 30 m1. of thionyl chloride was refluxed for2 hours and distilled to yield 3.9 g. of a-methoxyphenylacetonitrile,b.p. l20.123C. at 19 mm.

2. a-Methoxy3-trifluoromethylphenylacetonitrile, 2.5 g., b.p. ll5l20C.at 17 mm., was prepared as in Example E-l using 4 g. ofa-methoxy-3-trifluoromethylphenylacetamide and 20 ml. of thionylchloride.

3. a-n-Butoxyphenylacetonitrile, 4.9 g., b.p. l46l48C. at 16 mm.,.wasprepared as in Example E-l using 7 g. of a-n-butoxyphenylacetamide and20 ml. of thionyl chloride.

4. 4-Chloro-ot-methoxyphenylacetonitrile, b.p. 99l03C. at 0.7 mm., wasprepared in 59% yield by dehydration ofa-methoxy-4-chlorophenylacetamide by heating it with thionyl chloride inbenzene until the theoretical quantity of water was removed.

5. a-Ethoxyphenylacetonitrile, b.p. lllO6C. at 0.4 mm., was prepared asin Example E-4 in 73% yield by heating a-ethoxyphenylacetamide withthionyl chloride in benzene.

F. OTHER 2-(LOWER-ALKOXY )-2-Ar-ALKANEN1TR1LES 1.2-Ethoxy-2phenylbutanenitrile To a stirred solution of 32.2 g. ofa-ethoxyphenylacetonitrile in 100 ml. of tetrahydrofuran, kept at about510C. using an ice bath, was added dropwise under nitrogen 27 g. ofpotassium tertiarybutoxide as a w/v solution in tetrahydrofuran. Afterthe addition, which took thirty minutes, the reaction mixture wasstirred an additional minutes in ice; the ice bath was removed and themixture stirred an additional 15 minutes. To the reaction mixture keptat about 15-20C. was added dropwise over a period of about 15 minutes 39g. of ethyl iodide. The ice bath was removed and the reaction mixturestirred for 45 minutes. Then enough glacial acetic acid was added untilthe reaction mixture was no longer basic to wet pH paper (about 0.5ml.). The mixture was then filtered through sintered glass and theresidual salts thoroughly washed with ether. The combined washings andfiltrate were distilled in vacuo to yield 23.8 g. of 2-ethoxy-2-ethoxy-2-phenylbutanenitrile, b.p. 1131l4C. at 12 2.2-(4-Chlorophenyl)-2-ethoxybutanenitrile, b.p. l28129C. at 9 mm., 22.3g., was prepared as in Example F-l by first adding a solution of 39.0 g.of 4- chloro-a-ethoxyphenylacetonitrile in 30 ml. of tetrahydrofurandropwise over a period of 45 minutes to a solution containing 28.0 g. ofpotassium tertiary-butoxide in 200 ml. of tetrahydrofuran, maintainingthe mixture at about 50-10C.; stirring the mixture with cooling foranother hour; then adding dropwise over a period of about 30 minutes tothe stirred solution cooled to about 10C. a solution of 42.1 g. of ethyliodide in ml. of tetrahydrofuran; and working up the reaction mixture asin Example F-l.

Following the procedure described above in Example F-l and usingcorresponding molar equivalent quantities of the appropriatea-(lower-alkoxy)-Aracetonitrile and lower-alkyl or lower-alkenyl halide,the following 2-(lower-alkoxy)-2-Ar-alkanenitriles are obtained:2-ethoxy-2-pheny1propanenitrile using a-ethoxyphenylacetonitrile andmethyl iodide; 2-(4- chlorophenyl)-2-ethoxypentanenitrile using4-chloroa-ethoxyphenylacetonitrile and n-propyl iodide; 2-(3-chlorophenyl)-2-ethoxyhexanenitrile using3-chloro-acthoxyphenylacetonitrile and n-butyl bromide; 2-ethoxy-2-phenyloctanenitrile using a-ethoxyphenylacetonitrile andn-hexyl bromide; and, 2-ethoxy- 2-(3-fluorophenyl)-4-pentenenitrileusing a-ethoxy-S- fluorophenylacetonitrile and allyl bromide.

IMIDAZOLINES l 2-(0z-Ethoxybenzyl)-2-imidazoline To a mixture containing16.1 g. of a-ethoxyphenylacetonitrile and 7.2g. of ethylenediamine (1.2-cthanediamine) was added five drops of carbon disulfide and the reactionmixture was heated at -99C. for 6 hours and then allowed to coolwhereupon the reaction mixture solidified. The reaction mixture wastaken up with benzene-isopropyl alcohol (5:1 v/v). The resultingsolution was filtered. the filtrate concentrated and n-hexane added tocloudiness. The solution was allowed to cool to room temperature and thewalls of the glass container scratched with a glass rod. The resultingcrystalline precipitate was collected and recrystallized once frombenzene and once from methylene chlorideether to yield 7.5 g. of2-(a-ethoxybenzyl)-2- imidazoline, m.p. 123.0l25.4C. (corr.).

2. Z-(a-Ethoxybenzyl)-5-methyl-2-imidazoline, 6.6 g., m.p. 102.0l05.6C.(corr. was prepared as in Example G-l using 16.1 g. ofa-ethoxyphenylacetonitrile, 8.9 g. of 1,2-propanediamine and five dropsof carbon disulfide, and recrystallizing once from benzene-nhexane andonce from methylene chloride-n-hexane.

3. 2-(2,6-Dichloro-oz-ethoxybenzyl)-2-imidazoline To a mixturecontaining 1 1.5 g. of 2,6- dichlorophenyl-a-ethoxyacetonitrile and 6 g.of ethylenediamine was added three drops of carbon disulfide andresulting mixture was heated with stirring under an atmosphere ofnitrogen at about 135C. for 18 hours. The reaction mixture was taken upwith a mixture of benzene and water; the benzene layer was separated,washed 3 times with water and then extracted with three 50 ml. portionsof 2N hydrogen chloride. The acidic solution was washed with ether andthen made basic with 35% aqueous sodium hydroxide solution. Theseparated solid was extracted with benzene and the benzene removed bydistilling in vacuo. The resulting solid was dissolved in hottetrahydrofuran, the hot solution treated with decolorizing charcoal andfiltered, and the filtrate concentrated and n-hexane added to theconcentrate. The solution was allowed to cool and the resultingprecipitate was collected to yield 7.5 g. of2-(2,6-dichloro-a-ethoxybenzyl)- 2- imidazoline, m.p. l04107C.

4. 2-(2-Ch1oro-a-ethoxybenzyl)-2-imidazoline, 12.2 g., m.p. 84-87C., wasprepared as in Example G-3 using 19.6 g. of2-chloro-a-ethoxyphenylacetonitrile, 8 g. of ethylenediamine, threedrops of carbon disulfide and a heating period of 12 hours on a steambath. 1n the work-up, the reaction mixture was taken up with 1:1 (v/v)benzene-ether and water, and the aqueous layer was extracted with ether.The combined organic extracts were washed with brine and extracted threetimes with 2N hydrogen chloride. The acidic extract was extracted withether and then made strongly basic with 35% aqueous sodium hydroxidesolution. The basic mixture was extracted 3 times with ether. The etherextract was washed with brine, dried over anhydrous potassium carbonateand evaporated to yield a solid, which was recrystallized frombenzene-n-hexane and dried at 40C. in vacuo to yield said product.

5. 2-(3,4-Dich1oro-a-ethoxybenzyl)-4,4(or 5,5 )-dimethyl-2-imidazolineTo a mixture containing 23.0 g. of 3,4-dichlorphenyla-ethoxyacetonitrileand 10.6 g. of 2-methyl-l,2-

propanediamine was added five drops of carbon disulfide and theresulting mixture was heated under an atmosphere of nitrogen at 140C.for about 18 hours. The reaction mixture was allowed to cool and waspoured into benzene. The solution was washed with water and thenextracted with 6N hydrogen chloride. The acidic extract was madestrongly basic with 35% aqueous sodium hydroxide solution, whilecooling. and the separated basic product was extracted with ether. Theother solution was washed successively with water and brine, dried overanhydrous magnesium sulfate and then concentrated in vacuo to yield asolid. The solid was dissolved in boiling n-hexane. The hexane solutionwas treated with decolorizing charcoal, filtered, concentrated to avolume of about 200 ml. and allowed to cool. The separated solid wascollected, washed with n-hexane and dried at 60C. for about 26 hours.There was thus obtained 18.2 g. of 2-(3,4-dichloro-aethoxybenzyl )-4,4(or 5 ,5 )-dimethy1-2imidazoline, m.p. 11l-114C.

6. Z-(wn-Propoxybenzyl)-2imidazoline A mixture containing 17.5 g. ofampropoxyphenylacetonitrile, 7.2 g. of ethylenediamine and five drops ofcarbon disulfide was heated at 140C. for 2% hours under an atmosphere ofnitrogen and allowed to cool whereupon the mixture solidified. The solidwas dissolved in ethyl acetate and the resulting solution was washedfree of ethylenediamine with water and then extracted with 1:1 (v/v)hydrochloric acid. The acidic solution was made strongly basic with 35%aqueous sodium hydroxide solution and the liberated basic product wastaken up in ethyl acetate. The ethyl acetate solution was washedsuccessively with water and brine, dried over anhydrous magnesiumsulfate and evaporated in vacuo to remove the solvent. The remainingsolid was recrystallized from either using decolorizing charcoal anddried in vacuo at 60C. for 18 hours to yield 14.0 g. of2-(a-n-propoxybenzyl)-2- imidazoline, m.p. 82-84C.

7. 2-(a-Methoxybenzyl)-2-imidazoline, 8.1 g., 79-80C., was prepared asin Example G-2 using 14.7 g. of a-methoxyphenylacetonitrile, 7.2 g. ofethylenediamine, five drops of carbon disulfide, a heating period of 12hours on a steam bath and two recrystallizations from methylenechloride-n-hexane.

7a. Z-(a-Methoxybenzyl)-2-imidazoline A mixture containing 3.9 g. ofa-methoxyphenylacetonitrile, 1.6 g. of 95% ethylenediamine andapproximately 0.3 g. of hydrogen sulfide was heated at 1 l0115C. untilthe evolution of ammonia had ceased (45 minutes). The reaction mixturewas allowed to cool and treated with dilute aqueous hydrochloric acid;decolorizing charcoal was added and the mixture filtered. The filtratewas made alkaline with aqueous sodium hydroxide solution and extractedwith ether. The ether extract was distilled in vacuo to yield 1.9 g. of2-(a-methoxybenzyl)-2imidazoline, b.p. 114-117C. at 0.25 mm.

8. 2-(3,4-Dichloro-a-ethoxybenzyl)-2-imidazoline, 6.4 g., m.p. 75-76C.,was prepared as in Example G-l using 14.9 g. of3,4-dichloro-aethoxyphenylacetonitrile, 4.7 g. of ethylenediamine, fourdrops of carbon disulfide, a heating period of 6 hours at about 100C.,four recrystallizations from benzene-n-hexane using decolorizingcharcoal the last time and drying in vacuo at 40C. for several days.

2-[a-Ethoxy-( lnaphthyl)methyl]-4,4(or 5,5)-dimethyl-2-imidazoline, 10.6g., m.p. 9l-93C., was prepared as in Example G-3 using 21 g. ofaa-ethoxy-l-naphthylacetonitrile, 10.6 g. of 2-methyl-l ,2-propanediamine, five drops of carbon disulfide. a heating period of 24hours, at 140C.. three recrystallizations n-hexane using decolorizingcharcoal and drying in vacuo over-night at 60C.

10. 2-la-Methoxy-(1-naphthyl)methyl]-2- imidazoline A mixture containing9.8 g. of a-methoxy-lnaphthylacetonitrile, 3.6 g. of ethylenediamine andthree drops of carbon disulfide was heated on a steam bath for about 15hours. The reaction mixture was allowed to cool to room temperature andthen dissolved in isopropyl acetate. The isopropyl acetate solution waskept over-night at 0C., and the resulting crystalline precipitate wascollected and the mother liquor was saved. The crystalline precipitatewas dried at 60C. in vacuo for two days to yield 3 g. of2-[a-methoxy(lnaphthyl)methyl]2-imidazoline, m.p. 86C. A small sample ofsaid crystalline product was treated with a solution of hydrogenchloride and ether followed by evaporation of solvent and triturationwith acetonitrile whereupon there were obtained crystals of 2-[ozmethoxy-(1-naphthyl)methyl]-2-imidazoline hydrochloride. The abovemother liquor was then treated with ethereal hydrogen chloride andevaporated in vacuo. The remaining residue was taken up with ml. ofboiling acetonitrile and hot solution filtered. The filtrate wasconcentrated and seeded while hot with said crystalline2-1amethoxy(l-naphthyl)methyl]-2- imidazoline hydrochloride and thenallowed to cool to room temperature. The resulting crystalline productwas collected, washed with acetonitrile and then recrystallized bydissolving it in 40 ml. of boiling isopropyl alcohol, addingdecolorizing charcoal, filtering while hot, concentrating the filtrateand then adding acetone until crystallization starts. The mixture wasallowed to cool and the crystalline product that separated was collectedand dried in vacuo at 60C. to yield 3.5 g. of 2-[a-methoxy(l-naphthyl)methyl]-2- imidazoline hydrochloride m.p. 235237C.

11. 2-(a-Ethoxybenzyl)-4,4(or 5,5)-dimethyl-2- imidazoline, 4.7 g., m.p.73C., was prepared as in Example G-3 using 16.1 g. ofa-ethoxyphenylacetonitrile, 12 ml. of 2-methyl-l,2-propanediamine, fivedrops of carbon disulfide and a heating period of 18 hours at C. withstirring. The reaction mixture was taken up with chloroform rather thanbenzene, the product was triturated twice with n-pentane rather thanrecrystallizing it and was dried at 0.1 mm. at room temperature overphosphorus pentoxide.

12. 2-(ct-Methoxy-3-trifluoromethylbenzyl)-2- imidazoline Into a mixturecontaining 3.7 g. of a-methoxyS-trifluoromethylphenylacetonitri1e and1.2 g. of ethylenediamine was bubbled briefly hydrogen sulfide and themixture was then heated at-100110C. for 30 minutes. Fractionationyielded 2.6 g. of 2-(a-methoxy-3- trifluoromethylbenzyl)-2-imidazoline,b.p. 1l71 19C. at 0.35 mm. An ether solution of the base treated withhydrogen chloride yielded 2-(a-methoxy-3-trifluoromethylbenzyl)-2-imidazoline hydrochloride, m.p. 206-208C..after recrystallization from isopropyl alcoholether.

13. 2-(4-Chloro-oz-methoxybenzyl)-2-imidazolidine, as its hydrochloride,m.p. .194195C., was prepared as in Example G-7a using correspondingmolar equivalent quantities of a-methoxy-4- chlorophenylacetonitrile,ethylenediamine and hydrogen sulfide.

l4. 2-(a-n-Butoxybenzyl)-2-imidazoline, as its hydrochloride, 2.5 g.,m.p. l61162C. after recrystallization from isopropyl alcohol-ether. wasprepared as in Example G-l 2 using 4.8 g. ofa-nbutoxyphenylacetonitrile, 1.6 g. of ethylenediamine, a small quantityof hydrogen sulfide and a heating period of 1 lO-1 15C. for 25 minutes.The compound in free base form melted at 8083C. after recrystallizationfrom n-heptane.

l5. 2-(a-Ethoxybenzyl)-l-methyl-2-imidazoline, b.p. l06-l10C. at 0.3mm., was prepared as in Example G-l2 using corresponding molarequivalent quantities of a-ethoxyphenylacetonitrile, N-methylethylenediamine and hydrogen sulfide.

l6. l-n-Butyl-2-( a-ethoxybenzyl)-2-imidazoline, 16.0 g., b.p. 100110C.at 0.025 mm., was obtained as in Example G-3 using 16.1 g. ofa-ethoxyphenylacetonitrile, 17.4 g. of N-nbutylethylenediamine, fourdrops of carbon disulfide and a heating period of 48 hours at 140C.

17. 2-(a-Ethoxy-2-methoxybenzyl)-2-imidazoline A mixture containing 10.0g. of a-ethoxy-Z- methoxyphenylacetonitrile, 8 g. of ethylenediamine andfour drops of carbon disulfide was heated at 120C. for 16 hours. Theexcess diamine was removed by heating the reaction mixture at 100C. and30 mm. for 1 hour. The residue was taken up in ether and filtered. Theether solution was extracted with three 25 ml. portions of 2N hydrogenchloride and once with brine. The

. combined aqueous extracts including the brine were made basic with 35%aqueous sodium hydroxide solution while cooling in an ice bath and theresulting mixture was extracted three times with chloroform. Thechloroform extract was dried over anhydrous potassium carbonate, treatedwith decolorizing charcoal and filtered. The filtrate was evaporated toremove the chloroform thereby yielding 10.5 g. of 2-(aethoxy-2-methoxybenzyl)-2-imidazoline. The latter compound was mixed with 45 ml.of 1.0M phosphoric acid in absolute ethanol and the resulting mixturewas evaporated. Z-propanol was added and evaporated off to leave acrystalline product which was recrystallized from 100 ml. of absoluteethanol using decolorizing charcoal to yield 8.4 g. of2-(a-ethoxy-Z-methoxybenzyl)-2- imidazoline phosphate m.p. l84-I86C.

l8. 2(a-Ethoxy-a-ethylbenzyl)-2-imidazoline, m.p. 9798C., 4.5 g., wasprepared as in Example G-3 using 9.0 g. of2-ethoxy-2-phenylbutanenitrile, 5.0 g. of ethylenediamine, six drops ofcarbon disulfide and an initial heating period of 5 hours at 150C. withstirring. Additional portions of ethylenediamine totaling 3.5 g. wereperiodically added to the reaction mixture which was heated anadditional 1 hours at l30l50C. The reaction mixture was worked up as inExample G-3.

Following the procedure described in Example G, e.g., G-3. G-5 or 6-6,using corresponding molar equivalent quantities of the appropriatea-(lower-a1koxy)- Ar-acetonitrile or 2-(lower-alkoxy)-Ar-alkanenitrileand 1,2-alkanediamine, the followingZ-[a-(loweralkoxy)-Ar-methyll-2-imidazolines are obtained: 2-( 3-fluoro-a-n-propoxybenzyl )4,4(or 5 ,5 )-dimethyl-2- imidazoline usingoz-ethoxy-B-fluorophenylacetonitrile and 1-methyl-1,2-propanediamine;2-(a-ethoxy4- isopropylbenzyl)-1-ethyl-2-imidazoline using a-ethoxy-4-isopropylphenylacetonitrile and N- ethylethylenediamine;2-[a-ethyl-a-S-indanylmethyl]- l,4,5-trimethyl-2-imidazoline usinga-ethoxy-S- indanyl-acetonitrile and N-methyl-Z,S-butanediamine;l-n-butyl-2-( a-ethoxy-4-methoxybenzyl )-4.4(or

5.5 )dimethyl-Z-imidazoline using a-ethoxy-4- methoxyphenylacetonitrileand N'-butyl-2-methyll ,2- propanediamine; 2-(2,4-dibromo-0z-ethoxybenzyl N,4,4-trimethyl-2-imidazoline using2,4-dibromo-aethoxyphenylacetonitrile and N ',2-dimethyl-1 ,2-propanediamine; 2-(a,3,4-triethoxybenzyl)-1-methyl- 2-imidazoline usinga,3,4-triethoxyphenylacetonitrile and N-methylethylenediamine;4-ethoxy-2-(a-ethoxy- 3-diethylaminobenzyl)1-isopropyl-4-methyl-2-imidazoline using a-ethoxy-3- diethylaminophenylacetonitrile andN'-isopropyl-2- methyl-1,2-butanediamine; 2-( a-ethoxy- 3-f1uorobenzyl)-4,4,5,5-tetramethyl-2-imidazoline usinga-ethoxy-3-fluorophenylacetonitrile and 2,3-dimethyl- 2,3-butanediamine;2-(a-ethoxy-4-ethylbenzyl)-5- ethyl-l,5-dimethyl-2-imidazoline usingoz-ethoxy4- ethylphenylacetonitrile and N,2-dimethyl-l ,2-butanediamine; 2-(a-n-butoxy-4-methylmercaptobenzyl)-2imidazoline usinga-n-butoxy-4-methylmercaptophenylacetonitrile and ethylenediamine;2-(aethoxy-4-methylsulfonylbenzyl)-1,4-diethyl-2- imidazoline usingoz-ethoxy-4-methylsulfonylphenylacetonitrile andN'-ethyl-1,Z-butanediamine; 2-[a-(4-biphenylyl-a-ethoxy)methyl]-2-imidazoline usinga-ethoxy-4-biphenylylacetonitrile and ethylenediamine;2-(4-chloro-a-n-hexoxybenzyl)-2-imidazoline using4-chloro-a-n-hexoxyphenylacetonitrile and ethylenediamine;2-(a-ethoxy-a-ethylbenzyl)-2- imidiazoline usingZ-ethoxy-Z-phenylbutanenitrile and ethylenediamine;2-(a-allyl-a-ethoxy-3-fluorobenzyl)- Z-imidazoline using2-ethoxy-2-(3-fluorophenyl)-4- pentenenitrile and ethylenediamine; and,2-(a-ethoxya-n-hexylbenzyl)-2-imidazoline using 2-ethoxy-2-phenyloctanenitrile and ethylenediamine.

H. 2-[ALPHA-( LOWER-ALKOXY )-Ar-METHYL]- l,4,5,6-TETRAHYDROPYRIMID1NES 1. 2-(a-Ethoxybenzyl)-1,4,5,6tetrahydropyrimidine To a mixture containing 16.1 g. ofoz-ethoxyphenylacetonitrile and 8.9 g. of 1,3-propanediamine was addedwith swirling five drops of carbon disulfide. The resulting reactionmixture was heated on a steam bath with stirring for 6 hours and thenallowed to stand at room temperature overnight (about 15 hours),whereupon solidification resulted. The solid was taken up in benzene andthe benzene solution filtered. The filtrate was concentrated and to itwas added n-hexane. The resulting crystalline precipitate was collected,recrystallized from methylene chloride-n hexane, washed with Nhexane anddried at 50C. and 20 mm. to yield 12.1 g. of 2-( a-ethoxybenzyl 1,4,5,6- tetrahydropyrimidine, m.p. 10l.4-103.6C. (corr.). 2-(a-Ethoxybenzyl)- l ,4,5,6-tetrahydropyrimidine hydrochloride, m.p.l43l47C., was prepared by treating a chilled solution ofZ-(a-ethoxybenzyU-1,4,5,6- tetrahydropyrimidine in methanol with asolution of hydrogen chloride in isopropyl alcohol, evaporating off thesolvent, recrystallizing the residue from acetone and drying theresulting salt at 60C. in vacuo.

2. 2-[a-Methoxy-( l-naphthyl)methyl]- 1,4,5 ,6tetrahydropyrimidine, 4.7g., m.p. l02.5103.5C., was prepared as in Example H-l using 9.8 g. ofoz-methoxy-l-naphthylacetonitrile, 8.9 g. of l,3propanediamine, fourdrops of carbon disulfide, a heating period of 24 hours and successiverecrystallization from isopropyl acetate and tetrahydrofuranisopropylacetate.

. 2-(4-Chloro-a-ethoxybenzyl )-l ,4,5.6- tetrahydropyrimidine, 21 g.,m.p. 9396C., was prepared as in Example l-l-l using 39.1 g. of4-chloro-aethoxyphenylacetonitrile, 17.8 g. of 1,3- propanediamine, sixdrops of carbon disulfide and recrystallization from benzene-n-hexane.

4. 2-(2,6-Dichloro-a-ethoxybenzyl)-1,4,5,6- tetrahydropyrimidine, 3.5g., m.p. 120-123C., was prepared as in Example l-l-l using 17.9 g. of2,6- dichloro-a-ethoxyphenylacetonitrile, 7 g. of 1,3- propanediarnine,four drops of carbon disulfide and the following work-up of the reactionmixture. The solid reaction mixture was taken up in a 1 to 1 mixture(v/v) of ether-benzene plus some water. The organic layer was separated,washed three times with water and then extracted with 2N aqueoushydrogen chloride. The acidic solution was washed with ether, mixed withice and made basic with 10% aqueous sodium hydroxide solution. Thecrystalline precipitate was taken up in benzene, the benzene solutiondried over anhydrous potassium carbonate and then concentrated in vacuofollowed by addition of nhexane. The resulting crystalline product wascollected and dried in vacuo at 60C.

5. 2-[a-Ethoxy-(1-naphthyl)methyl]-1,4,5,6- tetrahydropyrimidine, 17.2g., m.p. 101103C., was prepared as in Example H-4 using 25.2 g. ofa-ethoxyl-naphthylacetonitrile, 10.8 g. of 1,3-propanediamine, sevendrops of carbon disulfide and a reflux period of 3 hours. In thework-up, chloroform was used instead of ether-benzene and the productwas recrystallized from n-hexane. 2-[oz-Ethoxy-(l-naphthyl)methyl]-1,4,5,6-tetrahydropyrimidine hydrochloride, m.p. 227-229C., was preparedby treating an anhydrous ether solution of the basic compound with anexcess of anhydrous ethereal hydrogen chloride, recrystallizing the salttwice from acetonitrile using decolorizing char coal and drying it invacuo at 75C. for 18 hours.

6. 2-(a-Ethoxy-3-fluorobenzyl)-1,4,5,6- tetrahydropyrimidine, 13.9 g.,m.p. 9294C., was prepared as in Example l-l-l using 17.9 g. ofa-ethoxy-3- fluorophenylacetonitrile, 9.0 g. of 1,3-propanediamine,three drops of carbon disulfide, a heating period of 2 /2 hours at 140C.under an atmosphere of nitrogen and recrystallization from other usingdecolorizing charcoal.

7. 2-(2-Chloro-a-ethoxybenzyl)-1,4,5 ,6- tetrahydropyrimidine, 11.9 g.,m.p. ll104C., was prepared in Example l-l-5 using 19.6 g.2-chloro-aethoxyphenylacetonitrile, g. of 1,3-propanediamine, threedrops of carbon disulfide, a heating period of 12 hours on a steam bath,ether in the workup and recrystallization from benzene-n-hexane.

8. 2-( a-Ethoxy-4-methylbenzyl 1 ,4,5,6 tetrahydropyrimidine, 8.5 g.,m.p. 7273C., was prepared as in Example H5 using 17.5 g. of oz-ethoxy-4-methylphenylacetonitrile, 10.1 g. of 1,3-

propanediamine, eight drops of carbon disulfide and a heating period of5 hours at 140C.

9. Z-(a-Ethoxybenzyl 1 -methyl-l ,4,5,6- tetrahydropyrimidine, 20.7 g.,b.p. 8795C. at 0.02 mm., was prepared as in Example H-8 using 25.8 g. ofa-ethoxyphenylacetonitrile, 19 ml. of N-methyl-l,3- propanediamine, fourdrops of carbon disulfide and a heating period of 26 hours at 130C.

10. 2-(3,4-Dichloro-a-ethoxybenzyl)-1,4,5,6- tetrahydropyrimidine, 10.0g., m.p. 9092C., was prepared as in Example H-5 using 23.0 g. of3,4-dichloroa-ethoxyphenylacetonitrile, 9.0 g. of 1.3- propanediamine,three drops of carbon disulfide. a heating period of 2 /2 hours at 140C.under a nitrogen atmosphere, ethyl acetate in the work-up and successiverecrystallizations from cyclohexane (with charcoal), n-hexane (withcharcoal) and ether.

1 l. 1,4,5,6-Tetrahydro-2-(a-n-propoxybenzyl pyrimidine, 13.8 g., m.p.86.588.5C., was prepared as in Example H-lO using 17.5 g. ofa-npropoxyphenylacetonitrile, 9.0 of 1,3-propanediamine. five drops ofcarbon disulfide, a heating period of 4 hours at 140C. andrecrystallization from ether using decolorizing charcoal.

12. 2-[a-Ethoxy-(2-naphthyl)methyl]- 1 ,4,5,6- tetrahydropyrimidine, 9.4g., m.p. ll5117C., was prepared as in Example H-lO using 10.56 g. ofa-ethoxy-2-naphthylacetonitrile, 4.45 g. of 1,3- propanediamine, twodrops of carbon disulfide, a heating period of 5 /2 hours at 140C. andrecrystallization from cyclohexane using decolorizing charcoal.

13. 2-(a-Ethoxy-4-isopropylbenzyl)-l ,4,5,6- tetrahydropyrimidine, 1 1.2g., m.p. l07.5C., was prepared as in Example H-10 using 20 g. ofa-ethoxy-4- isopropylphenylacetonitrile, 9 g. of 1,3- propanediamine,five drops of carbon disulfide, a heating period of 5 hours at C. andrecrystallization from acetonitrile using decolorizing charcoal.

l4. 2-(a-n-Butoxybenzyl)-l,4,5,6- tetrahydropyrimidine, 16.7 g., m.p.5462C., was prepared as in Example H-IO using 18.9 g. ofa-nbutoxyphenylacetonitrile, 9.0 g. of 1,3- propanediamine, three dropsof carbon disulfide and a heating period of 4 hours at 140C. The lightyellow waxy product, which was not recrystallized, was dried at roomtemperature and 0.03 mm. for 44 hours.

15. 2-1a-Ethoxy-(5indanyl)methyl]-1,4,5,6- tetrahydropyrimidine To amixture containing 20.1 g. of a-ethoxy-S- indanylacetonitrile and 9 g.of 1,3-propanediamine was added three drops of carbon disulfide and theresulting mixture was stirred under nitrogen at l35140C. for 4 /2 hours.The volatile liquids were evaporated off at 100C. and 15 mm. over afifteen minute period on a rotary evaporator and the residue was dilutedwith benzene. The benzene solution was washed with brine and extractedwith three 100 ml. portions of 2N aqueous collected. washed withn-hexane and dried in vacuo at 50 C. to yield 15.2 g. of 2-la-ethoxy-(5-indanyl)methyl]-l,4,5,6-tetrahydropyrimidine, m.p. 69-75C.

l6. Z-(a-EthoxybenzyU-l ,4,5 .6-tetrahydro- ,5- dimethylpyrimidine, 24.8g., m.p. 9294C., was prepared as in Example H-l using 23.5 g. ofa-ethoxyphenylacetonitrile, 16 g. of 2,2-dimethyl-l ,3- propanediamine,four drops of carbon disulfide, a heating period of 6 hours at l35140C.under an atmosphere of nitrogen, hot n-hexane to dissolve the cooledsolid reaction mixture and recrystallization from nhexanc usingdecolorizing charcoal. A solution containing 4 g. of2-(a-ethoxybenzyl)-1,4,5,6-tetrahydro- 5,5-dimethylpyrimidine in 100 ml.of isopropyl alcohol was treated with 5 ml. of concentrated hydrochloricacid and the resulting solution evaporated to dryness. The solid residuewas recrystallized from 60 ml. of acetone to yield 3.9 g. ofZ-(a-ethoxybenzyU-l,4,5,6-' tetrahydro-S,S-dimethylpyrimidinehydrochloride, m.p. l81-183C.

l7. l-n-Butyl-2-(a-ethoxybenzyl)-1,4,5,6- tetrahydropyrimidine, 17.5 g.,b.p. 103-110C. at 0.0075-0.01 mm., was prepared as in Example H-S using16.] g. of a-ethoxyphenylacetonitrile, 13.0 g. ofN-n-butyl-l,3-propanediamine, four drops of carbon disulfide and etherin the work-up.

18. 2-(4-Chloro-a-ethoxybenzyl)-5-ethyll ,4,5 ,6-tetrahydro-5-methylpyrimidine, 5.6 g., m.p. 8687C., was prepared as inExample H-l6 using 15.6 g. of 4- chloro-a-ethoxyphenylacetonitrile, 10.2g. of 2-ethyl- Z-methyl- 1 ,3-propanediamine, four drops of carbondisulfide, a heating period of 17 hours at l35-140C. and threerecrystallizations from n-hexane.

19. 2-(4-Ch1oro-a-ethoxybenzyl )-l ,4,5,6-tetrahydro-5,5-dimethylpyrimidine, 11.5 g., m.p. 114-1l5C., was prepared as inExample H-l6 using 19.6 g. of 4-chloroa-ethoxyphenylacetonitrile, 11.2g. of 2,2-dimethyl- 1,3-propanediamine, four drops of carbon disulfide,a heating period of 17 hours at 135C. and two recrystallizations fromether-n-hexane.

20. 2-(2-Chloro-a-ethoxybenzyl)-1,4,5,6-tetrahydro-5,5-dimethylpyrimidine, 11.1 g., m.p. l116C., was prepared as in Example1-1-4 using 19.6 g. of 2-chloroa-ethoxyphenylacetonitrile, 11.2 g. of2,2-dimethyl- 1,3-propanediamine, four drops of carbon disulfide, aheating period of 135140C. for 17 hours, ether in the work-up andrecrystallization from ether-n-hexane.

21. 2-( a-EthoxybenzyD-S-ethyll ,4,5,6-tetrahydro- S-methylpyrimidine,12.5 g., b.p. 132135C. at 0.15 mm., was prepared as in Example H-16using 12.9 g. of a-ethoxyphenylacetonitrile, 10.2 g. of2-ethyl-2-methyl-l ,3-propanediamine, four drops of carbon disulfide, aheating period of 17 hours at l35140C. and then distilling the reactionmixture under vacuum to yield said product.

22. 2-(a-Ethoxy-4-isopropylbenzyl)-1,4,5,6-tetrahydro-5,S-dimethylpyrimidine, 14.5 g., b.p. 137-- 1 39C. at 0.045mm., was prepared as in Example H-20 using 20.3 g. of a-ethoxy-4-isopropylphenylacetonitrile, 11.2 g. of 2.2-dimethyl-1.3-propanediamine, four drops of carbon disulfide, a heating period of17 hours at 135-140C., ether in the workup and distilling said productunder vacuum.

23. 2-(a-Ethoxy-4-methoxybenzyl)-1,4,5,6-tetrahydro-5,S-dimethylpyrimidine, 10.4 g., b.p. 138-l43C. at 0.02 mm.,was prepared as in Example 5.5-dimethylpyrimidine, 7.0 g., m.p. 88-89C.,was

prepared as in Example H-4 using 17.9 g. of a-ethoxy-3-fluorophenylacetonitrile, 1 1.2 g. of 2,2-dimethy1-l .3propanediamine, four drops of carbon disulfide, a heating period of 17hours at C, benzene in the workup and two recrystallizations fromn-hexane using decolorizing charcoal.

25. 2-[a-Ethoxy-( 1-naphthyl)methyl]-l.4.5.6-tetrahydro-S,S-methylpyrimidine 5.4 g., m.p. l06-l07C., was prepared asin Example H-16 using 21.1 g. of a-ethoxy-l-naphthylacetonitrile, 1 1.2g. of 2,2-dimethyl-1,3-propanediamine, five drops of carbon disulfide, aheating period of 5 hours at l35-140C., and successiverecrystallizations from ethern-hexane, aqueous methanol and n-hexane.

26. 2-(a-Ethoxybenzyl)- 1 ,4,5 ,6-tetrahydro-5- pyrimidinol, 9.4 g.,b.p. 148150C., at 0.01 mm., was prepared as in Example 1-1-21 using 16.1g. of a-ethoxyphenylacetonitrile, 10.8 g. of 2-hydroxy-1,3-propanediamine, four drops of carbon disulfide,.a heating period of 15hours on a steam bath and distillation of said product under vacuum.2-(a-Ethoxybenzyl)- l,4,5,6-tetrahydro-5-pyrimidinol hydrochloride, m.p.152-156C., was prepared by treating an ethanolic solution of the basicproduct with ethereal hydrogen chloride, collecting the hydrochlorideand triturating it with acetone and then recrystallizing it twice fromether-acetone.

27. 2-(a-Ethoxy-a-ethylbenzyl)-1,4,5,6- tetrahydropyrimidine, 20.9 g.,m.p. 78.5-81.0C., was prepared as in Example H-4 using 23.8 g. ofa-ethoxya-phenylbutyronitrile (2-ethoxy-2- phenylbutanenitrile), l 1 g.of 1,3-propanediamine, four drops of carbon disulfide, and a heatingperiod of 20 hours at C., ether in the work-up and recrystallizationfrom n-hexane.

28. 2-[a-Methoxy-(4-biphenylyl)methyl]-1,4,5 ,6- tetrahydropyrimidine,was prepared as follows: A mixture containing 16.5 g. of a-methoxy-4-biphenylylacetic acid, 7.4 g. of 1,3-propanediamine and 500 m1. ofxylene was stirred under reflux with a continuous water separatorattached to the reaction vessel. The heating was continued for 14 hoursat which time 3.8 m1. of water had been collected. The reaction mixturewas allowed to cool while stirring and then filtered. The filtrate waswashed successively with water and 10% aqueous potassium carbonatesolution, and then acidified with aqueous hydrochloric acid. The organiclayer was separated and extracted three times with 2N aqueous hydrogenchloride. The acidic extract was extracted with ether and then madebasic with aqueous sodium hydroxide solution. The basic solution wasextracted with chloroform; the chloroform solution was dried overanhydrous potassium carbonate and then evaporated in vacuo. The residuewas crystallized from isopropyl acetate-n-hexane and dried in vacuo at50C. to yield 3.8 g. of 2-[a-methoxy-(4- biphenylyl)methyl]-l,4,5,o-tetrahydropyrimidine, m.p. 108-1 10C.

29. 2-(a-Ethoxy-4-methoxybenzyl)-1,4,5,6- tetrahydropyrimidine, 10.64g., b.p. l35145C. at 0.06 mm. and m.p. 52-56C., was prepared as inExample H-21 using 19.1 g. of a-ethoxy-4 methoxyphenylacetonitrile, 9.0g. of 1,3- propanediamine, five drops of carbon disulfide and a heatingperiod of 6 hours at 140C.

30. 2-(a-Methoxybenzyl)- 1 ,4,5,6- tetrahydropyrimidine Hydrogen sulfidewas bubbled through a mixture containing 6.4 g. ofa-methoxyphenylacetonitrile and 3.7 g. of 1,3-propanediamine. Theensuing reaction. from which ammonia was evolved, was vigorous andcooling was necessary to control it. After the initial reaction hadsubsided, the mixture was heated at 95C. for 15 minutes, cooled andtreated with dilute aqueous hydrochloric acid. The resulting aqueoussolution was clarified by extraction with ether, after which it was madealkaline and extracted with ether. The ether was distilled off and theresidue distilled in vacuo to yield 5.3 g. of 2-(0z-methoxybenzyl)- 1,4,5,6- tetrahydropyrimidine, b.p. l281 29C. at 0.4 mm. and m.p. 66-68C.Treatment of an ether solution of this basic compound with etherealhydrogen chloride yielded Z-(a-methoxybenzyl )-1 ,4,5 ,6-tetrahydropyrimidine hydrochloride, m.p. 207208C. afterrecrystallization from isopropyl alcohol-ether.

31. 2-(3-Chloro-a-ethoxybenzyl)-l ,4,5,6- tetrahydropyrimidine, 9.3 g.,m.p. 8687C.. was prepared as in Example H-4 using 19.6 g. of3-chloro-ozethoxyphenylacetonitrile, 8.2 g. of 1,3- propanediamine, fourdrops of carbon disulfide, a reaction period of 3 hours at l35l45C.,ether in the work-up and two recrystallizations from n-hexane usingdecolorizing charcoal during the first recrystallization.

32. 2-(4-Chloro-a-ethoxybenzyl)-1,4,5,6-tetrahydro- 5-methylpyrimidine,4.3 g., m.p. 808lC., was prepared as in Example l-l-l6 using 19.6 g. of4-chloro-ozethoxyphenylacetonitrile, 10.0 g. of 2-methyl-1.3-propanediamine, five drops of carbon disulfide, a heating period of 6 /2hours at l35140C. and recrystallizing the cooled reaction mixtureseveral times from nhexane using decolorizing charcoal during the firstrecrystallization.

3 3. 2-(0z-Ethoxybenzyl)-1,4,5,6-tetrahydro-5- methylpyrimidine, 5.5 g.,m.p. 9798C., was prepared as in Example H-5 using 16.] g. ofa-ethoxyphenylacetonitrile, g. of 2-methyl-1,3- propanediamine, fivedrops of carbon disulfide, a heating period of 5 hours at l35l40C. undernitrogen, ether in the work-up and three recrystallizations fromn-hexane using decolorizing charcoal the first time.

34. Z-(a-EthoxybenzyU-l,4,5,6-tetrahydro-5- methoxypyrimidine, 7.3 g.,b.p. l40-l46C. at 0.10-O.l 1 mm. (solidified to a waxy solid of m.p.63-69C.), was prepared as in Example H-S using 13.4 g. ofa-ethoxyphenylacetonitrile, 9.2 g. of Z-methoxy- 1,3-propanediamine, sixdrops of carbon disulfide, a heating period of 8 hours at l38l40C. undernitrogen and ether in the work-up.

35. 2-(a-Ethoxy-Z-methoxybenzyl)-l ,4,5,6-

tetrahydropyrimidine, 9.4 g., m.p. 80-82C., was prepared as in ExampleH-4 using 19.1 g. of a-ethoxy2- methoxyphenylacetonitrile, 10 g. of 1,3-propanediamine, five drops of carbon disulfide, a heating period of 18hours at l35l45C. and recrystalliof a-ethoxyphenylacetonitrile, 14.3 g.of 2.2-diethyl- 1,3-propanediamine, six drops of carbon disulfide and aheating period of 21 hours at -135C. under nitrogen. Ether was used inthe work-up and the product was distilled under reduced pressure.

37. 2-(4-Chloro-a-ethoxy-a-ethylbenzyl)- 1 ,4,5,6-tetrahydro-S,S-dimethylpyrimidine, m.p. l24l25C., 4.52 g., was preparedas in Example H-20 using 22.3 g. of2-(4-chlorophenyl)-2-ethoxybutanenitrile, 12.2 g. of2,2-dimethyl-l.3-propanediamine. six drops of carbon disulfide andinitially a heating period of 17 hours at l50l52C. Additional portionsof carbon disulfide (total of 35 drops) and 2.2-diethyl-l.3-pr0panediamine (total of 7.5 g.) were added to the reaction mixturewhich was heated an additional 7 days at about C. Ether was used in thework-up and the product was recrystallized from n-hexane usingdecolorizing charcoal.

38. 2-(4-Chloro-a-ethoxybenzyl)-5,5-diethyll,4,5,6-tetrahydropyrimidineTo a mixture containing 19.6 g. of 4-chloro-aethoxyphenylacetonitrileand 14.3 g. of 2,2-diethyl-l,3- propanediamine was added with stirringunder an atmosphere of nitrogen, six drops of carbon disulfide and theresulting mixture was stirred under an atmosphere of nitrogen whileheating at 130-140C. for 17 hours. The reaction mixture was thendistilled under reduced pressure to distill off any low boiling diamineintermediate and was then dissolved in 500 ml. of ether. The ether wasextracted with two 500 ml. portions of 6N hydrochloric acid. The acidicextract was washed with ether, made basic with 35% aqueous sodiumhydroxide solution and the mixture extracted thoroughly with ether. Theether extract was dried over anhydrous sodium sulfate, distilled invacuo to remove the ether and then distilled in vacuo to yield 12.2 g.of 2-(4-chloro-aethoxybenzyl )-5 ,5-diethyl-1,4,5,6'tetrahydropyrimidine, b.p. 148l50C. at 0.02 mm. The product'solidifiedon standing at room temperature, and was then recrystallized fromn-hexane, using decolorizing charcoal, to yield 7.9 g. of whitecrystalline 2(4-chloro-0z-ethoxybenzyl)-5,S-diethyl-l,4,5,6-tetrahydropyrimidine, m.p. 6870C. after drying in vacuo for 24 hours at25C.

39. 2-(4-Benzyloxy-a-ethoxybenzyl)-1,4,5,6- tetrahydropyrimidine Amixture containing 28.7 g. of oz-4-benzyloxy-aethoxyphenylacetonitrile,11 g. of 1,3-propanediamine and four drops of carbon disulfide washeated with stirring at l0Ol 10C. for 16 hours. The reaction mixture waspoured into water and a 1 to 1 mixture (by volume) of ether and benzene.The organic layer was separated, washed with water and extracted threetimes with 2N hydrochloric acid. Excess 35% aqueous sodium hydroxidesolution was added with cooling to the aqueous phase and the alkalinemixture was extracted 3 times with chloroform. The chloroform extractwas dried over anhydrous potassium carbonate while treating withdecolorizing charcoal, filtered and evaporated in vacuo to remove thechloroform, thereby yielding 31.9 g. of 2-( 4-benzyloxy-a-ethoxybenzyl)-l ,4,5 ,6- tetrahydropyrimidine.

40. 2-(a-Ethoxy-4hydroxybenzyl )-l ,4,5,6- tetrahydropyrimidine Asolution containing 9.7 g. of 2-(4-benzyloxy-acthoxybenzyl)-l,4,5.6-tetrahydropyrimidine in 250 ml. of absolute ethanol was mixedwith 25 ml. of 5.6N hydrogen chloride in absolute ethanol and theresulting mixture was refluxed for 15 minutes and then evaporated invacuo to remove the ethanol. The residue, a foamy material, was taken upwith 50 ml. of 5.6N hydrochloric acid in absolute ethanol; the mixturewas re fluxed for an additional 1 hour and 45 minutes and evaporated invacuo to remove the ethanol. After examination of the nuclear magneticresonance spectrum of the residue had indicated only about 50%debenzylation of the starting material, the residue was taken up in 100ml. of methanol, 600 mg. of 60% palladium chloride was added and themixture hydrogenated at 40 p.s.i. for 8 hours at room temperature. Thereaction mixture was filtered and the filtrate evaporated in vacuo toremove the solvent to leave 5.8 g. of2-(aethoxy-4-hydr0xybenzyl)-1,4,5,6- tetrahydropyrimidine as itshydrochloride, an amorphous white solid.

41. 2-[a-Ethoxy-2(and tetrahydropyrimidine A 5.0 g. portion of2(a-ethoxybenZyl)-1,4,5,6- tetrahydropyrimidine hydrochloride was addedwith swirling and cooling to 25 ml. of concentrated sulfuric acid. Theacidic solution was cooled to about -5C. and 5 ml. of fuming nitric acidwas added slowly with swirling whereupon the temperature rose to about18C. The reaction mixture was cooled in an ice bath for 2 hours, pouredonto ice and made basic with a slight excess of 35% aqueous sodiumhydroxide solution. The alkaline solution was extracted withcholoroform; the extract dried over anhydrous potassium carbonate whiletreating with decolorizing charcoal, filtered and evaporated in vacuo toremove the chloroform. The oily residue was dissolved in isopropylalcohol and the solution treated with ml. of 5.6N hydrogen chloride inethanol and the solvents removed by distilling in vacuo. lsopropylalcohol was added to the residue and then removed by distilling invacuo. The residue was crystallized from acetone-ether, thenrecrystallized from acetonitrile-acetone and dried in vacuo at 50C. toyield 1.5 g. of a mixture of 2-(aethoxy-2-nitrobenzyl)-l,4,5,6-tetrahydropyrimidine hydrochloride and2-(a-ethoxy-4-nitrobenzyl)-1,4,5,6- tetrahydropyrimidine hydrochloride,m.p. 202208C. The nuclear magnetic resonance spectrum indicates themixture to consist of about 80% of the 2-nitro compound and about 20% ofthe 4-nitro compound.

42. 2-(a-Ethoxy'l ,4,5,6-tetrahydrobenzyl)-l ,4,5,6-

tetrahydropyrimidine To a stirred mixture containing 24 g. ofa-ethoxy-3- cyclohexenylacetonitrile, g. of 1,3-propanediamine under anatmosphere of nitrogen was added six drops of carbon disulfide and theresulting mixture heated with stirring under an atmosphere of nitrogenfor 44 hours at l35-145C. The reaction mixture was distilled underreduced pressure to remove any excess diamine and the residual oilymaterial was dissolved in ether. The other solution was extracted with2N hydrogen chloride. The acidic extract was washed with ether and thenmade basic with 3N sodium hydroxide solution and the resulting milkysuspension extracted several times with ether (total of 1000ml). Theether extract was dried over anhydrous magnesium sulfate and distilledin vacuo to remove the ether and the residue distilled to yield afraction boiling at 103105C. at 0.02 mm. This fraction, which partiallysolidified, was distilled again to yield 10.15 g. of2-(a-ethoxy-1,4,5,6- tetrahydrobenzyl)-l,4,5,o-tetrahydropyrimidine,b.p.

4)-nitrobenzyl 1 ,4,5 ,6-

9396C. at 0015-0018 mm. The product solidified on standing, m.p. 7677C.

43. 2-(3-Chloro-a-ethoxybenzyl)-1,4,5,6tetrahydro-5,5-dimethylpyrimidine, m.p. 82-83C., 8.0 g., was prepared as in ExampleH-20 using 13.8 g. of 3-chloroa-ethoxyphe'nylacetonitrile, 9.0 g. of2,2-dimethyl-l,3- propanediamine, six drops of carbon disulfide andrecrystallization from n-hexane using decolorizing charcoal.

44. 2-(3-Ch1oro-a-ethoxybenzyl)-5,5-diethyl-1.4-5,6-tetrahydropyrimidine, b.p. l36138C. at 0012-0015 mm., 7.2 g., wasprepared as in Example H-21 using 13.8 g. of 3-chloro-aethoxyphenylacetonitrile, l 1.7 g. of 2,2-diethyl-l,3- propanediamine,six drops of carbon disulfide and three vacuum distillations of theproduct.

45. 2-(a-Ethoxy-3-fluorobenzyl)-5,5-diethyl-l ,4,5,6-tetrahydorpyrimidine, b.p. 124-126C. at 0.01 50.030 mm., 8.4 g., wasprepared as in Example H-2l using 14.0 g. ofa-ethoxy-3-fluorophenylacetonitrile, 11.0 g. of 2,2-diethyl-1,3-propanediamine and six drops of carbon disulfide.

46. 2-( 2-Amino-4-chloro-a-ethoxybenzyl)-1,4,5,6-tetrahydro-5,5-dimethylpyrimidine is prepared by catalytichydrogenation of an ethanol solution of 2-(4-chloro-a-ethoxy-Z-nitrobenzyl)-1,4,5,6-tetrahydro-5,5-dimethylpyrimidine in the presence of two equivalents of hydrogenchloride over 10% palladium on charcoal at three atmospheres of hydrogenat room temperature. After completion of the hydrogenation, the reactionmixture is filtered and the ethanol removed from the filtrate to yieldthe product in the form of its dihydrochloride.

47. 2-[4-(and 2)-Amino-a-ethoxybenzyl]-l,4,5,6- tetrahydropyrimidine isobtained as in Example H-46 using a corresponding molar equivalentquantity of 2- [oz-ethoxy-2'( and 4)'nitrobenzyl]-l ,4,5,6-tetrahydropyrimidine (from Example H-41).

48. 2-(a-Ethoxycyclohexylmethyl)-1,4,5 ,6- tetrahydropyrimidine In ahydrogenation vessel was placed 30 ml. of absolute ethanol and l g. ofplatinium dioxide. The dioxide was reduced under hydrogen until uptakewas com plete. To the platinium suspension was added a solutioncontaining 4.0 g. of 2-(a-ethoxyl ,4,5 ,6- tetrahydrobenzyl)-l ,4,5,6-tetrahydropyrimidine, 30 ml. of ethanol and 5 ml. of 4.9N ethanolichydrogen chloride, thereby yielding a mixture having a pH of 2.Hydrogenation was accomplished at atmospheric pressure and roomtemperature over a period of about 6 hours. The catalyst was filteredoff through a pad of infusorial earth and the filtrate was distilled at50C. and 10 mm. to remove the solvents. The remaining oily residue wasdissolved in 10 m1. of ice water and made basic with 20% aqueous sodiumhydroxide solution. The alkaline solution was extracted with ether. Theether extract was dried over anhydrous magnesium sulfate and the etherdistilled off in vacuo. The oily residue was dissolved in 50 ml. ofn-hexane, and the solution treated with decolorizing charcoal andfiltered. The filtrate was concentrated to a volume of about 20 ml. andcooled. The crystalline precipitate was collected and dried in vacuo for4 hours to yield 1.82 g. of 2-(aethoxycyclohexylmethyl)-1,4,5,6-tetrahydropyrimidine, m.p. 99100C.

49. 2-(a-Ethoxy-3-fluoro-4-methoxybenzyl)-1,4,5,6- tetrahydropyrimidine,6.9 g., b.p. 137l40C. at

0.06-0.07 mm. (solidified to a waxy solid of m.p. 77-79C.), was preparedas in Example H-4 using 14.? g. ofa-ethoxy-3-fluoro-4-methoxyphenylacetonitrile, 6.0 g. ofl,3-propanediamine, six drops of carbon disultide and a heating periodof 17 hours.

50. 2-(a-Ethoxy-3-fluoro-4-methoxybenzyl)-l,4.5.6-tetrahydro-S,S-dimethylpyrimidine, 16.2 g., b.p. 148-l49C. at 0.07-0.08mm. (solidified, m.p. 83-85C.). was prepared as in Example H-4 using20.9 g. of a-ethoxy-3-fluoro-4-methoxyphenylacetonitrile, 11.2 g. of2,2-dimethyl-l,3-propanediamine. six drops of carbon disulfide and aheating period of 20 hours.

51. 2-(3-Chloro-a-ethoxybenzyl)-5-ethyl-1,4,5,6-tetrahydrO-S-methylpyrimidine, 15.2 g., b.p. 142145C. at 0.03 mm., wasprepared as in Example H-15 using 19.6 g. of3-chloro-aethoxyphenylacetonitrile, 12.0 g. 2-ethyl-2-methyl- 1,3-propanediamine, six drops of carbon disulfide, a heat ing period of 16hours at 135140C., extraction of the product with ether and vacuumdistillation of the product.

52. 5-Ethyl-2-(3-fluor0-a-ethoxybenzyl)-1,4,5,6-tetrahydro-S-methylpyrimidine, 19.0 g., m.p. 59-61C., was prepared as inExample H-51 using 17.9 g. of oz-ethoxy-3-fluorophenylacetonitrile, 12.8g. of 2- ethyl-2-methyl-l,3-propanediamine, six drops of carbondisulfide and vacuum distillation (b.p. 129132C. at 0.03 mm.) of theproduct which solidified at room temperature.

53. 2-(or'Ethoxy-3-fluoro-4-methoxybenzyl)-5-ethyl-1,4,5,6-tetrahydro-S-methylpyrimidine, 16.0 g., b.p. l56-l57C. at 0.1mm., was prepared as in Example H-51 using 20.9 g. ofa-ethoxy-3-fluoro-4- methoxyphenylacetonitrile, 12.8 g. of2-ethyl-2-methyl-l,3propanediamine and six drops of carbon disulfide.

54. 2-(3,4-Dichloro-a-ethoxybenzyl)-l,4,5,6-tetrahydro-S-methylpyrimidine, 7.1 l g., m.p. l-l0l.5C., was prepared asin Example 15 using 15.0 g. 3,4-dichloro-a-ethoxyphenylacetonitrile,6.32 g. of 2-methyl-1,3-propanediamine, five drops of carbon disulfide,a heating period of 18 hours at 140C., extraction of the product withethyl acetate, vacuum distillation of the product (b.p. l68178C. at 0.03mm.) and recrystallization of the solidified distillate from cyclohexaneusing decolorizing charcoal.

55. 2-(4-Chloro-a-ethoxybenzyl)-1,4,5,6-tetrahydro- -n-propylpyrimidine,11.6 g., m.p. 8385C., was prepared as Example H-54 using 16.1 g. of4-chloro-aethoxyphenylacetonitrile, 10.5 g. of 2-n-propyl-1,3-propanediamine, five drops of carbon disulfide, a heating period of 6hours at 140C., vacuum distillation of the product (b.p. l40-144C. at0.02 mm.) and recrystallization of the solidified distillate fromn-hexane.

56. 2(4Ch1oro-a-ethoxy-3-nitrobenzyl )-l ,4,5 ,6-tetrahydro-S,S-dimethylpyrimidine To 50 ml. of chilled concentratedsulfuric acid was added in portions with stirring and cooling 7 g. of2-(4- chloro'a-ethoxybenzyD-l ,4.5,6-tetrahydro-5.6- dimethylpyrimidine,maintaining the temperature below 18C. To the mixture was added 2.2 g.of potassium nitrate whereupon the reaction temperature rose to about32C. The reaction mixture was quickly cooled below 20C. and held therefor about 30 minutes. The mixture was then allowed to warm up to roomtemperature and was stirred for about hours. The mixture was then pouredonto ice. A small amount of gummy precipitate was removed by extractionwith a large volume of ethyl acetate. The remaining acid solution wasmixed with more ice and made strongly basic with 35% aqueous sodiumhydroxide solution. The basic solution with extracted with chloroform.The chloroform solution was dried over anhydrous potassium carbonate andevaporated in vacuo to remove the chloroform. The remaining oilsolidified and was then treated with ether and a small amount of residuewas filtered off. The ether filtrate was concentrated and treated withn-hexane whereupon there separated a crystalline product which wascollected to yield 3.2 g. 2-(4-chloro-a-ethoxy-3-nitrobenzyl)-1,4,5 ,6-tetrahydro-S.S-dimethylpyrimidine, m.p. 1 l01 13C.

57. 2-(3-Amino-4-chloro-a-ethoxybenzyl)-1.4.5.6-tetrahydro-S,S-dimethylpyrimidine was obtained by catalytichydrogenation of 3.25 g. of 2-(4-chloro-aethoxy-3-nitrobenzyl )-l ,4,5,6-tetrahydro-5 ,5- dimethylpyrimidine in 100 ml. of ethanol using 0.25g. of 10% palladium-on-charcoal, 25 mg. of cuprous chloride and aninitial pressure of 39 p.s.i. of hydrogen.

58. 2-[4-Chloro-a-ethoxy-3-(hydroxyamino)benzyl]- 1,4,5 ,6-tetrahydro-5,S-dimethylpyrimidine A reaction mixture containing 35.5 g. of2-(4-ch1oroa-ethoxy-3-nitrobenzyl )-l ,4,5 ,-tetrahydro-S ,5-dimethylpyrimidine, 35 m1. of hydrazine, 350 ml. of absolute ethanol andabout one-fourth of a teaspoon of Raney nickel was swirled as thereaction caused brisk effervescence and a temperature rise. When thetemperature had risen to about 45C., cooling was applied to keep thetemperature below 50C. The reaction mixture was swirled for about 5minutes, after which the reaction had subsided, and then filteredthrough infusorial earth. The filtrate was cooled in an ice bath forabout 1 hour. The resulting precipitate was collected and washedsuccessively with cold ethanol and cold isopropyl alcohol to yield 20.0g. of 2-[4- chloro-a-ethoxy-3-(hydroxyamino)benzy1]1 ,4,5 ,6-tetrahydro-S,S-dimethylpyrimidine, m.p. l72l74C. with charring.

Following the procedure described in Example l-l, e.g., H-l H-4,H-5,H-1O or H-l6, using corresponding molar equivalent quantities of theappropriate a-(1ower-alkoxy)-Aracetonitri1e or 2-(lower-alkoxy)-2-Ar-alkanenitrile and 1,3-alkanediamine, the following2-[a-(lower-alkoxy)-Ar-methyl]-1,4,5,6- tetrahydropyrimidines areobtained: 2-(3-chloro-aethoxybenzyl)-1,4,5,6-tetramethyl-l,4,5,6-tetrahydropyrimidine using 3-chloro-aethoxyphenylacetonitrile andN',2-dimethyl-2,4- pentanediamine; 2-(2-chloro-a,4-diethoxybenzyl)-4,6-dimethyl- 1 ,4,5,6-tetrahydropyrimidine using2-chloroa,4-diethoxyphenylacetonitrile and 2,4- pentanediamine;2-(2,4-dibromo-a-ethoxybenzyl)- 4(or6)-ethyl-5-methyl-1,4,5.6-tetrahydropyrimidine using2,4-dibromo-oc-ethoxyphcnylacetonitrile and 2-methyl-l,3-pentanediamine; 2-(a-ethoxy-4- dimethylaminobenzyl)-5-ethyl-4(or6)-n-propyl- 1,4,5 ,6-tetrahydropyrimidine using a-ethoxy-4-dimethylaminophenylacetonitrile and 2-methyl-l,3- hexanediamine;2-(oz-ethoxy-3-fluorobenzyl)-l-nhexyl-l,4,5,6-tetrahydropyrimidine usinga-ethoxy-3- fluorophenylacetonitrile and N-n-hexyll ,3- propanediamine;2-(a-ethoxy-4-ethylbenzyl)-5- isobutyl-S-methyl-l,4,5,6-tetrahydropyrimidine using a-ethoxy-4-ethylphenylacetonitrile and2-isobu tyl-2- methyl-l ,3-prop'anediamine; 2-( a-ethoxy-3 ,4,5-

29 trimethoxybenzyl )--n-butyl-5-ethyl-l ,4,5 ,6- tetrahydropyrimidineusing a-ethoxy-3,4,5-trimethoxyphenylacetonitrile and2-n-butyl-2-ethyl-l ,3- propanediamine;2-(4-n-butoxy-a-ethoxybenzyl)-5,5- dimethyl-l,4,5,o-tetrahydropyrimidineusing 4-nbutoxy-a-ethoxyphenylacetonitrile and 2,2-dimethyl-1,3-propanediamine; 2-( a-ethoxy-2,4- dimethylbenzyl )-5,5-diethyll,4.5,6- tetrahydropyrimidine using a-ethoxy-ZA-dimethylphenylacetonitrile and 2.2-diethyl-l ,3- propanediamine;2-(a-ethoxy-4-fluoro-2- methoxybenzyl)-5-methyl-5-n-propyl-1.4.5.6-tetrahydropyrimidine using a-ethoxy 5-fluoro-2-methoxyphenylacetonitrile and 2-methyl-2-n-propyl- 1,3-propanediamine;2-( a-ethoxy-4-methylmercaptobenzyl)-5,5-dimethyl-l,4,5,6-tetrahydropyrimidine usinga-ethoxy-4-methylmercaptophenylacetonitrile and2,2dimethyl-l,3-propanediamine; Z-(a-ethoxy-2,4,6-trimethylbenzyl)-5-methyl-l ,4,5 ,6- tetrahydropyrimidine usinga-ethoxy-2,4,6- trimethylphenylacetonitrile and Z-methyl-l ,3-propanediamine; 2-(a-ethoxy-4-n-hexoxybenzyl)-l,4,5,6-tetrahydropyrimidine using a-ethoxy-4-n-hexoxyphenylacetonitrileand 1,3-propanediamine; 2-(aethoxy-3 ,5-diiodobenzyl )-5,5-dimethyl- 1,4,5,6-

tetrahydropyrimidine using a-ethoxy-3 ,5- diiodophenylacctonitrile and2,2-dimethyl-l ,3- propanediamine; 2-(4-n-butylmercapto-aethoxybenzyl)-5,5-dimethyl-l ,4,5,6-

tetrahydropyrimidine using 4-n-butylmercapto-aethoxyphenylacetonitrileand 2,2-dimethyl-l ,3- propanediamine; 2-(a-ethoxy-4-methylsulfonylbenzyl )-5 ,5-dimethyl-l ,4,5,6-tetrahydropyrimidine usinga-ethoxy-4-methylsulfonylphenylacetonitrile and 2,2- dimethyl-l,3-propanediamine; 2-(a-ethoxy-4- ethylsulfonylbenzyl )-5 ,5 -dimethyl-l,4,5,6- tetrahydropyrimidine usinga-ethoxy-4-ethylsulfonylphenylacetonitrile and 2,2-dimethyl-l ,3-propanediamine; 2-(a-ethoxy-4-nitrobenzyl)-5,5- dimethyl-l,4,5,6-tetrahydropyrimidine using a-ethoxy- 4-nitrophenylacetonitrileand 2,2-dimethyl-l ,3- propanediamine; 2-(4-amino-a-ethoxybenzyl)-5,5-dimethyl-l,4,5,6-tetrahydropyrimidine was prepared by treating thecorresponding 2-(a-ethoxy-4- nitrobenzyl)-5,5-dimethyl-l,4,5,6-tetrahydropyrimidine with a reducing agent effective to reduce nitrogroups to amino groups, e.g., iron and hydrochloric acid or by catalytichydrogenation in the presense of two molar equivalents of hydrogenchloride using palladium on charcoal; 2-(a-ethoxy-3-trifluoromethylbenzyl)-5,5-dimethyl-1,4,5,6- tetrahydropyrimidine usinga-ethoxy-3-trifluoromethylphenylacetonitrile and 2,2-dimethyl-l ,3-propanediamine; 2-(4-chloro-a-hexoxybenzyl)-5,5-dimethyl-l,4,5,o-tetrahydropyrimidine using4-chloroa-n-hexoxyphenylacetonitrile and 2,2-dimethyl-l,3-propanediamine; 2-(a-ethoxy-a-methylbenzyl)- l,4,5.6-tetrahydropyrimidine using 2-ethoxy-2- phenylpropanenitrile andLB-propanediamine: 2-(4- chloro-a-ethoxy-a-n-propylbenzyl)-5-methyl- 1,4,5,6- tetrahydropyrimidine using ethoxypentanenitrile and Z-methyl-l,3- propanediamine;2-(a-n-butyl-3-chloro-acthoxybenzyl)-5.5-dimethyl-l,4,5,6-tetrahydropyrimidine using 2-(3-chlorophenyl)-2- ethoxyhexanenitrile and2,2-dimethyl-l ,3- propanediamine; 2-(a-allyl-a-ethoxy-3-fluorobenzyl)-2-(4-chlorophenyl)-2- l,4,5,6-tetrahydropyrimidine using 2-ethoxy-2-(3-fluorophenyl )-4-pentenenitrile and 1,3- propanediamine; 12-(a-ethoxy-a-n-hexylbenzyl)- l,4,5,-tetrahydropyrimidine usinga-ethoxy-aphenyloctanenitrile and 1,3-propanediamine;2-(acth0xy-3-fluoro-4-methoxybenzyl )-5 ,S-diethyl- 1 ,4,5,6-tetrahydropyrimidine using a-ethoxy-3-fluoro-4-methoxyphenylacetonitrile and 2,2-diethyl-l .3- propanediamine;2-(4-chloro-aethoxy-2-nitrobenzyl)-5,5-dimethyl-l,4,5,6-tetrahydropyrimidine using 4-chloro-a-ethoxy2-nitrophenylacetonitrile and 2.2- dimethyl-l,3-propanediamine.

The anti-inflammatory activity was measured by the inhibition ofcarrageenin-induced local foot edema in fasted rats generally accordingto the procedure of C. A. Winter et al., Proc. Soc. Exptl. & Med. l l I.544-547 (1962) as follows: Food is withdrawn from male albino ratsweighing approximately ll0-l24 gms., 18 hours prior to a single oralmedication of the test compound. Each compound is administered to atleast five rats. One hour following the medication, 0.05 ml. of 1%aqueous suspension of carrageenin is injected into the plantar tissue ofthe right hind foot. Three hours after injections, the rats aresacrificed and the hind feet cut off at the tibio-calcaneo-talar jointfor subsequent weighing. The observed difference between the averageedema weight of the control and medicated rats is expressed as per centinhibition of edema. When tested by the above-described procedure,2-[a-(loweralkoxy )-Ar-methyl]-2-imidazolines and l ,4,5 ,6-tetrahydropyrimidines of the invention were found to inhibit local edemadue to carrageenin-induced inflammation when administered at oral doselevels between about 6 and 400 mg./kg.

The hypoglycemic activity was measured by the per cent decrease in bloodglucose levels from premedicated blood glucose levels in fasted ratsgenerally according to the procedure of Dulin et al., Proc. Soc. Exptl.& Med. 107, 245 (1961), wherein glucoseprimed rats were bled from thetail vein at l, 2, 3 and 5 hours following medication. Hypoglycemicactivity is expressed as the per cent decrease in blood glucose from thecontrol animals at the same hour. When tested by this procedure, thecompounds of the invention were found to have hypoglycemic activity whenadministered at oral dose levels between about 10 and 1000 mgjkg.

The diuretic activity was measured by the natriuretic response producedin rats generally according to the procedure of Williamson et al., J.Pharm. & Exptl. Therap. 126, 82(1959), using male albino rats, -200 g.,which have been fasted overnight. The compound to be tested isadministered orally in 0.5% gum tragacanth in 0.85% NaCl at a volume of25 ml./l00 g. body weight. The compound is administered to six animalsat each dose level. Twelve control (no drug) animals and six animalstreated with 8 micromoles/kg. of hydrochlorothiazide are run in eachexperiment. A fixed molar dose schedule for drugs is used. The highestdose used is 50 micromoles/kg. Succeeding doses are 40% of eachpreceding dose. Testing of a compound is completed when it no longerproduced a natriuretic response which is significantly greater than thatof the non-drug-treated groups. The dose of drug which produced aresponse 0.50 times that of the reference drug, hydrochlorothiazide, isthen reported as the approximate minimal effective dose or for use byconventional pharmaceutical procedures:

that is, by dissolving or suspending them in a pharmaceuticallyacceptable vehicle, e.g., aqueous alcohol, glycol, oil solution, oroil-water emulsion, for parenteral or oral administration; byincorporating them in unit dosage form as tablets or capsules for oraladministration either alone or in combination with conventionaladjuvants, e.g., calcium carbonate, starch, lactose, talc, magnesiumstearate, gum acacia, and the like.

I claim:

1. A compound having the formula wherein R is alkyl having from 2 to 6carbon atoms,

R is hydrogen or lower-alkyl,

Y is alkylene of 3-8 carbon atoms in which 2 or 3 carbon atoms intervenebetween the valence linkages, and

Ar is phenyl, naphthyl, indanyl, cyclohexenyl, cyclohexyl and phenylsubstituted by two halo substituents or a single substituent selectedfrom halo, nitro, lower-alkyl or lower-alkoxy, said lower-alkoxy beingat only the para-position of phenyl.

2. Z-(a-Alkoxy-Ar-methyl)-2-imidazoline according to claim 1 wherein twocarbon atoms intervene between the valence linkages of alkylene.

3. 2-(oz-Alkoxy-Ar-methyl 1 ,4,5,6- tetrahydropyrimidine according toclaim 1 wherein three carbon atoms intervene between the valencelinkages of alkylene.

4. Z-(a-n-Propoxybenzyl)-2-imidazoline.

5. 2-(a-Ethoxy-3-fluorobenzyl)-l.4,5,6- tetrahydropyrimidine accordingto claim 3.

2-( 2-Chloro-a-ethoxybenzyl l ,4,5 .6 tetrahydropyrimidine according toclaim 3.

7. 2-(3-Fluoro-a-ethoxybenzyl)-l,4,5,6-tetrahydro-5,5-dimethylpyrimidine according to claim 3.

2-( 3-Chloro-a-ethoxybenzyl )-l ,4,5.6- tetrahydropyrimidine accordingto claim 3.

9. 2-(4-Chloro-0z-ethoxybenzyl )-5-ethyll ,4,5 ,6-tetrahydro-S-methylpyrimidine according to claim 3.

l0. 2-( a-Ethoxybenzyl )-l ,4,5 ,6-tetrahydro-5 ,5- dimethylpyrimidineaccording to claim 3.

ll. 2-(4-chloro-a-ethoxybenzyl)- l ,4,5,6-tetrahydro-5,5dimethylpyrimidine according to claim 3.

l 2. 2-( a-Ethoxy-a-ethylbenzyl l ,4,5,6- tetrahydropyrimidine accordingto claim 3.

l3. 2-(a-Ethoxybenzyl)l ,4,5,6- tetrahydropyrimidine according to claim3.

14. 2( 4-Chloro-a-ethoxybenzyl )-l ,4,5 ,6- tetrahydropyrimidineaccording to claim 3.

l5. 2-(2,6-Dichloro-a-ethoxybenzyl)-l ,4,5,6- tetrahydropyrimidineaccording to claim 3.

-1 6. 2'[a-Ethoxy-( l-naphthyl)methyl]- 1 ,4,5,6- tetrahydropyrimidineaccording to claim 3.

17. Z-(a-Ethoxybenzyl)-4,4(or 5,5)-dimethyl-2- imidazoline according toclaim 2.

l8. Z-(a-n-Butoxybenzyl )-1 ,4,5,6- tetrahydropyrimidine according toclaim 3.

l9. 2-(4-Chloro-a-ethoxybenzyl)-l ,4,5,6-tetrahydro- S-methylpyrimidineaccording to claim 3.

20. Z-(a-EthoxybenzyU-l ,4,5 ,6-tetrahydro-5- methylpyrimidine accordingto claim 3.

21. 2-( 3-Chloro-a-ethoxybenzyl)-5-ethyll ,4,5 ,6-

tetrahydro-5-methylpyrimidine according to claim 3.

in irm sums PA'IENT OFFICE CERTIFICATE OF CORRECTiQN PATENT N I 3 897431 DATED July 29., 1975 INVENTORy I Deriis M. Bailey it is ceitified213% am! appears in the above-identified paient and that sea-3 Le iielsPater? are hereby corrected as shown below;

Column 1, lines 16 thru 23, Formula I should read a Ar-CC Y r, *N RColumn 3, line 7, 'methoxyphenyl" should read 'methoxyphenyhand line 8,delete the before ethanenitrile'" Column 31, lines 27 thru 33, theformula should read En'gnccl and Scaled this fourth Day Of November 1975[SEAL] Arrest:

RUTH C. MASON C. MARSHALL DANN Arresting Officer (innmissinner nfParemsand Trademarks

1. A COMPOUND HAVING THE FORMULA AR-C(-O-R)(-R'')-C<(=N-Y-NH-) WHEREIN RIS ALKYL HAVING FROM 2 TO 6 CARBON ATOMS R'' IS HYDROGEN OR LOWER-ALKYL,Y IS ALKYLENE OF 3-8 CARBON ATOMS IN WHICH 2 OR 3 CARBON ATOMS INTERVENEBETWEEN THE VALENCE LINKAGES AND AR IS PHENYL NAPTHYL INDANYLCYCLOHEXENYL CYCLOHEXYL AND PHENYL SUBSTITUTED BY TWO HALO SUBSTITUTENTSOR A SINGLE SUBSTITUTUENT SELETED FROM HALO NITRO, LOWER-ALKYL ORLOWER-ALKOXY SAID LOWER-ALKOXY BEING AT ONLY THE PARA-OSITION OF PHENYL.2. 2-( Alpha -Alkoxy-Ar-methyl)-2-imidazoline according to claim 1wherein two carbon atoms intervene between the valence linkages ofalkylene.
 3. 2-( Alpha -Alkoxy-Ar-methyl)-1,4,5,6-tetrahydropyrimidineaccording to claim 1 wherein three carbon atoms intervene between thevalence linkages of alkylene.
 4. 2-( Alpha-n-Propoxybenzyl)-2-imidazoline.
 5. 2-( Alpha-Ethoxy-3-flUorobenzyl)-1,4,5,6-tetrahydropyrimidine according to claim3.
 6. 2-(2-Chloro- Alpha -ethoxybenzyl)-1,4,5,6-tetrahydropyrimidineaccording to claim
 3. 7. 2-(3-Fluoro- Alpha-ethoxybenzyl)-1,4,5,6-tetrahydro-5,5-dimethylpyrimidine according toclaim
 3. 8. 2-(3-Chloro- Alpha-ethoxybenzyl)-1,4,5,6-tetrahydropyrimidine according to claim
 3. 9.2-(4-Chloro- Alpha-ethoxybenzyl)-5-ethyl-1,4,5,6-tetrahydro-5-methylpyrimidine accordingto claim
 3. 10. 2-( Alpha-Ethoxybenzyl)-1,4,5,6-tetrahydro-5,5-dimethylpyrimidine according toclaim
 3. 11. 2-(4-chloro- Alpha-ethoxybenzyl)-1,4,5,6-tetrahydro-5,5-dimethylpyrimidine according toclaim
 3. 12. 2-( Alpha -Ethoxy- Alpha-ethylbenzyl)-1,4,5,6-tetrahydropyrimidine according to claim
 3. 13. 2-(Alpha -Ethoxybenzyl)-1,4,5,6-tetrahydropyrimidine according to claim 3.14. 2-(4-Chloro- Alpha -ethoxybenzyl)-1,4,5,6-tetrahydropyrimidineaccording to claim
 3. 15. 2-(2,6-Dichloro- Alpha-ethoxybenzyl)-1,4,5,6-tetrahydropyrimidine according to claim
 3. 16.2-( Alpha -Ethoxy-(1-naphthyl)methyl)-1,4,5,6-tetrahydropyrimidineaccording to claim
 3. 17. 2-( Alpha -Ethoxybenzyl)-4,4(or5,5)-dimethyl-2-imidazoline according to claim
 2. 18. 2-( Alpha-n-Butoxybenzyl)-1,4,5,6-tetrahydropyrimidine according to claim
 3. 19.2-(4-Chloro- Alpha -ethoxybenzyl)-1,4,5,6-tetrahydro-5-methylpyrimidineaccording to claim
 3. 20. 2-( Alpha-Ethoxybenzyl)-1,4,5,6-tetrahydro-5-methylpyrimidine according to claim3.
 21. 2-(3-Chloro- Alpha-ethoxybenzyl)-5-ethyl-1,4,5,6-tetrahydro-5-methylpyrimidine accordingto claim 3.